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1. What OPDIVO is and what it is used for
OPDIVO is a prescription medicine used to treat:
· adults and children 12 years of age and older with a type of skin cancer called melanoma.
o OPDIVO may be used alone or in combination with ipilimumab to treat melanoma that has spread or cannot be removed by surgery (advanced melanoma), or
o OPDIVO may be used alone to help prevent Stage IIB, Stage IIC, Stage III or Stage IV melanoma from coming back after it has been completely removed by surgery.
· Adults with non-small cell lung cancer (a type of lung cancer) prior to resection in adults (treatment prior to surgery is called neoadjuvant therapy).
· adults with a type of lung cancer called non-small cell lung cancer (NSCLC).
o OPDIVO may be used in combination with ipilimumab and 2 cycles of chemotherapy that contains platinum and another chemotherapy medicine, as the first treatment of your NSCLC when your lung cancer:
§ has spread or grown, or comes back, and
§ your tumor does not have an abnormal EGFR or ALK gene.
o OPDIVO may be used when your lung cancer:
§ has spread or grown, and
§ you have tried chemotherapy that contains platinum, and it did not work or is no longer working.
§ If your tumor has an abnormal EGFR or ALK gene, you should have also tried an approved therapy for tumors with these abnormal genes, and it did not work or is no longer working.
· adults with a type of cancer that affects the lining of the lungs and chest wall called malignant pleural mesothelioma.
o OPDIVO may be used in combination with ipilimumab as your first treatment for malignant pleural mesothelioma that cannot be removed by surgery.
· adults with kidney cancer (renal cell carcinoma).
o OPDIVO may be used in combination with ipilimumab in certain adults when their cancer has spread (advanced RCC), and you have not already had treatment for your advanced RCC.
o OPDIVO may be used in combination with cabozantinib when your cancer has spread (advanced RCC), and you have not already had treatment for your advanced RCC.
o OPDIVO may be used alone when your cancer has spread or grown after treatment with other cancer medicines.
· adults with a type of blood cancer called classical Hodgkin lymphoma.
o OPDIVO may be used if:
§ your cancer has come back or spread after a type of stem cell transplant that uses your own stem cells (autologous), and
§ you used the medicine brentuximab vedotin before or after your stem cell transplant, or
§ you received at least 3 kinds of treatment including a stem cell transplant that uses your own stem cells (autologous).
· adults with head and neck cancer (squamous cell carcinoma).
o OPDIVO may be used when your head and neck cancer:
§ has come back or spread, and
§ you have tried chemotherapy that contains platinum, and it did not work or is no longer working.
· adults with cancer of the lining of the urinary tract (urothelial carcinoma).
- OPDIVO may be used to help prevent cancer of the urinary tract from coming back after it was removed by surgery.
o OPDIVO may be used in combination with chemotherapy medicines cisplatin and gemcitabine as your first treatment when your urinary tract cancer has spread (metastatic) or cannot be removed by surgery.
- OPDIVO may be used when your urinary tract cancer has spread or grown (locally advanced or metastatic), and:
§ you have tried chemotherapy that contains platinum, and it did not work or is no longer working, or
§ your cancer worsened within 12 months of treatment with chemotherapy that contains platinum, either before or after surgery to remove your cancer.
· adults with cancer of the tube that connects your throat to your stomach (esophageal cancer).
o OPDIVO may be used to help prevent your esophageal or gastroesophageal junction cancer from coming back when:
§ your esophageal or gastroesophageal junction cancer has been treated with chemoradiation followed by surgery to completely remove the cancer, but
§ some cancer cells were still present in the removed tumor or lymph nodes.
o OPDIVO may be used in combination with chemotherapy that contains fluoropyrimidine and platinum when your esophageal cancer:
§ is a type called squamous cell carcinoma, and
§ cannot be removed with surgery (advanced), or has spread to other parts of the body (metastatic), and
§ you have not already had treatment for your advanced or metastatic esophageal cancer.
o OPDIVO may be used in combination with ipilimumab when your esophageal cancer:
§ is a type called squamous cell carcinoma, and
§ cannot be removed with surgery (advanced), or has spread to other parts of the body (metastatic), and
§ you have not already had treatment for your advanced or metastatic esophageal cancer.
o OPDIVO may be used alone when your esophageal cancer:
§ is a type called squamous cell carcinoma, and
§ cannot be removed with surgery, and
§ has come back or spread to other parts of the body after you have received chemotherapy that contains fluoropyrimidine and platinum.
· adults with cancer of the stomach (gastric cancer), cancer where the esophagus joins the stomach (gastroesophageal junction cancer), and in adults with esophageal adenocarcinoma.
o OPDIVO may be used in combination with chemotherapy that contains fluoropyrimidine and platinum when your gastric, gastroesophageal junction, or esophageal cancer:
§ cannot be removed with surgery, or
§ has spread to other parts of the body.
It is not known if OPDIVO is safe and effective in children younger than 12 years of age with melanoma.
It is not known if OPDIVO is safe and effective in children for the treatment of any other cancers
2. Before you use OPDIVO
You should not be given OPDIVO
· if you are allergic to nivolumab or any of the other ingredients of this medicine (listed in section 6 “Further information"). Talk to your doctor if you are not sure.
Warnings and Precautions
Tell your healthcare provider about all of your medical conditions, including if you:
· have immune system problems such as Crohn’s disease, ulcerative colitis, or lupus
· have received an organ transplant
· have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic)
· have received radiation treatment to your chest area in the past and have received other medicines that are like OPDIVO
· have a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndrome
Check with your doctor or nurse before you are given OPDIVO if:
· you have an autoimmune disease (a condition where the body attacks its own cells);
· you have melanoma of the eye;
· you were previously given ipilimumab, another medicine for treating melanoma, and experienced serious side effects because of that medicine;
· you have been told that your cancer has spread to your brain;
· you have any history of inflammation of the lungs;
· you have been taken medicines to suppress your immune system.
Complications of stem cell transplant that uses donor stem cells (allogeneic) after treatment with OPDIVO. These complications can be severe and can lead to death. Your healthcare provider will monitor you for signs of complications if you have an allogeneic stem cell transplant.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
Talk to your doctor before using OPDIVO as it may cause:
· Problems with your heart such as a change in the rhythm or rate of the heartbeat or an abnormal heart rhythm.
· Problems with your lungs such as breathing difficulties or cough. These may be signs of inflammation of the lungs (pneumonitis or interstitial lung disease).
· Diarrhea (watery, loose or soft stools) or any symptoms of inflammation of the intestines (colitis), such as stomach pain and mucus or blood in stool.
· Inflammation of the liver (hepatitis). Signs and symptoms of hepatitis may include abnormal liver function tests, eye or skin yellowing (jaundice), pain on the right side of your stomach area, or tiredness.
· Inflammation or problems with your kidneys. Signs and symptoms may include abnormal kidney function tests, or decreased volume of urine.
· Problems with your hormone producing glands (including the pituitary, the thyroid, the parathyroid and adrenal glands) that may affect how these glands work. Signs and symptoms that these glands are not working properly may include fatigue (extreme tiredness), weight change or headache, decreased blood levels of calcium and visual disturbances.
· Diabetes including a serious, sometimes life-threatening problem due to acid in the blood produced from diabetes (diabetic ketoacidosis). Symptoms may include feeling more hungry or thirsty than usual, need to urinate more often, weight loss, feeling tired or having difficulty thinking clearly, breath that smells sweet or fruity, a sweet or metallic taste in your mouth, or a different odor to your urine or sweat, feeling sick or being sick, stomach pain, and deep or fast breathing.
· Inflammation of the skin that can lead to severe skin reaction (known as toxic epidermal necrolysis and Stevens-Johnson syndrome). Signs and symptoms of severe skin reaction may include rash, itching, and peeling of the skin (possibly fatal).
· Inflammation of the muscles such as myocarditis (inflammation of the heart muscle), myositis (inflammation of the muscles) and rhabdomyolysis (stiffness in muscles and joints, muscle spasm). Signs and symptoms may include muscle pain, stiffness, weakness, chest pain, or severe fatigue.
· Solid organ transplant rejection.
· Graft-versus-host disease.
· Hemophagocytic lymphohistiocytosis. A rare disease in which our immune system makes too many of otherwise normal infection fighting cells called histiocytes and lymphocytes. Symptoms may include enlarged liver and/or spleen, skin rash, lymph node enlargement, breathing problems, easy bruising, kidney abnormalities, and heart problems.
Tell your doctor immediately if you have any of these signs or symptoms or if they get worse. Do not try to treat your symptoms with other medicines on your own. Your doctor may:
· give you other medicines in order to prevent complications and reduce your symptoms,
· withhold the next dose of OPDIVO,
· or stop your treatment with OPDIVO altogether.
Please note that these signs and symptoms are sometimes delayed, and may develop weeks or months after your last dose. Before treatment, your doctor will check your general health. You will also have blood tests during your treatment.
Children and adolescents
OPDIVO should not be used in children and adolescents below 18 years of age except for adolescents 12 years of age and older with melanoma.
Other medicines and OPDIVO
Before you are given OPDIVO, tell your doctor if you are taking any medicines that suppress your immune system, such as corticosteroids, since these medicines may interfere with the effect of OPDIVO. However, once you are treated with OPDIVO, your doctor may give you corticosteroids to reduce any possible side effects that you may have during your treatment and this will not impact the effect of the medicine.
Tell your doctor if you are taking or have recently taken any other medicines. Do not take any other medicines during your treatment without talking to your doctor first.
Pregnancy and breast-feeding
Tell your healthcare provider if you:
· are pregnant or plan to become pregnant. OPDIVO can harm your unborn baby.
Females who are able to become pregnant:
o Your healthcare provider should do a pregnancy test before you start receiving OPDIVO.
o You should use an effective method of birth control during treatment and for 5 months after your last dose of OPDIVO. Talk to your healthcare provider about birth control methods that you can use during this time.
o Tell your healthcare provider right away if you become pregnant during treatment with OPDIVO.
· are breastfeeding or plan to breastfeed. It is not known if OPDIVO passes into your breast milk. Do not breastfeed during treatment and for 5 months after your last dose of OPDIVO.
Driving and using machines
OPDIVO or OPDIVO in combination with ipilimumab may have a minor influence on the ability to drive and use machines; however, use caution when performing these activities until you are sure that OPDIVO does not adversely affect you.
OPDIVO contains sodium
Tell your doctor if you are on a low-sodium (low-salt) diet before you are given OPDIVO. This medicine contains 2.5 mg sodium (main component of cooking/table salt) in each mL of concentrate.
OPDIVO contains 10 mg sodium per 4 mL vial or 25 mg sodium per 10 mL vial, which is equivalent to 0.5% or 1.25% respectively, of the recommended maximum daily dietary intake of sodium for an adult.
You will also find key messages from this package leaflet in the patient alert card you have been given by your doctor. It is important that you keep this patient alert card and show it to your partner or caregivers.
3. How to use OPDIVO
· Your healthcare provider will give you OPDIVO into your vein through an intravenous (IV) line over 30 minutes.
· When OPDIVO is used alone, it is usually given every 2 weeks or 4 weeks depending on the dose you are receiving.
· When OPDIVO is used in combination with ipilimumab (except for treating NSCLC), OPDIVO is usually given every 3 weeks, for a total of 4 doses. Ipilimumab will be given on the same day. After that, OPDIVO will be given alone every 2 weeks or 4 weeks depending on the dose you are receiving.
· For NSCLC before you have surgery, OPDIVO is given in combination with chemotherapy every 3 weeks for 3 cycles.
· For NSCLC that has spread to other parts of your body, when OPDIVO is used in combination with ipilimumab, OPDIVO is given every 3 weeks, and ipilimumab is given every 6 weeks for up to 2 years. Your healthcare provider will determine if you will also need to receive chemotherapy every 3 weeks for 2 cycles.
· For malignant pleural mesothelioma, OPDIVO is given every 3 weeks and ipilimumab is given every 6 weeks for up to 2 years.
· For RCC, when used in combination with cabozantinib, OPDIVO is usually given every 2 weeks or 4 weeks depending on the dose you are receiving. Cabozantinib is given once daily by mouth.
· For UC that has spread to other parts of your body or cannot be removed by surgery, when OPDIVO is used in combination with chemotherapy medicines cisplatin and gemcitabine, OPDIVO is given every 3 weeks for up to 6 cycles. Chemotherapy will be given on the same day. After that, OPDIVO will be given alone every 2 weeks or 4 weeks depending on the dose you are receiving.
· When OPDIVO is used in combination with chemotherapy for treating esophageal squamous cell carcinoma (ESCC), OPDIVO is given either every 2 weeks or every 4 weeks, for up to 2 years.
· When OPDIVO is used in combination with ipilimumab for esophageal squamous cell carcinoma, OPDIVO is given every 2 weeks or 3 weeks and ipilimumab is given every 6 weeks for up to 2 years.
· For gastric cancer, gastroesophageal junction cancer and esophageal adenocarcinoma, when used in combination with fluoropyrimidine and platinum-containing chemotherapy, OPDIVO is given every 2 weeks or 3 weeks depending on the dose you are receiving, for up to 2 years. Chemotherapy will be given on the same day.
· Your healthcare provider will decide how many treatments you need.
· Your healthcare provider will do blood tests to check you for side effects.
· If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.
4. Possible side effects
OPDIVO is a medicine that may treat certain cancers by working with your immune system. OPDIVO can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or can lead to death. These problems may happen anytime during treatment or even after your treatment has ended. You may have more than one of these problems at the same time. Some of these problems may happen more often when OPDIVO is used in combination with another therapy.
Call or see your healthcare provider right away if you develop any new or worse signs or symptoms, including:
Lung problems.
· new or worsening cough
· shortness of breath
· chest pain
Intestinal problems.
· diarrhea (loose stools) or more frequent bowel movements than usual
· stools that are black, tarry, sticky, or have blood or mucus
· severe stomach-area (abdominal) pain or tenderness
Liver problems.
· yellowing of your skin or the whites of your eyes
· severe nausea or vomiting
· pain on the right side of your stomach area (abdomen)
· dark urine (tea colored)
· bleeding or bruising more easily than normal
Hormone gland problems.
· headaches that will not go away or unusual headaches
· eye sensitivity to light
· eye problems
· rapid heartbeat
· increased sweating
· extreme tiredness
· weight gain or weight loss
· feeling more hungry or thirsty than usual
· urinating more often than usual
· hair loss
· feeling cold
· constipation
· your voice gets deeper
· dizziness or fainting
· changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness
Kidney problems.
· decrease in your amount of urine
· blood in your urine
· swelling of your ankles
· loss of appetite
Skin problems.
· rash
· itching
· skin blistering or peeling
· painful sore or ulcers in mouth or nose, throat, or genital area
Problems can also happen in other organs and tissues. These are not all of the signs and symptoms of immune system problems that can happen with OPDIVO. Call or see your healthcare provider right away for any new or worsening signs or symptoms, which may include:
· Chest pain, irregular heartbeat, shortness of breath or swelling of ankles
· Confusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling or numbness of the arms or legs
· Double vision, blurry vision, sensitivity to light, eye pain, changes in eyesight
· Persistent or severe muscle pain or weakness, muscle cramps
· Low red blood cells, bruising
Getting medical treatment right away may help keep these problems from becoming more serious.
Your healthcare provider will check you for these problems during treatment with OPDIVO. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also need to delay or completely stop treatment with OPDIVO, if you have severe side effects.
OPDIVO can cause serious side effects.
· Severe infusion reactions. Tell your healthcare provider or nurse right away if you get these symptoms during an infusion of OPDIVO: | |
o chills or shaking o itching or rash o flushing o shortness of breath or wheezing | o dizziness o feel like passing out o fever o back or neck pain |
· Complications of stem cell transplant that uses donor stem cells (allogeneic). These complications can be severe and can lead to death. These complications may happen if you underwent transplantation either before or after being treated with OPDIVO. Your healthcare provider will monitor you for signs of complications if you have an allogeneic stem cell transplant.
The most common side effects of OPDIVO when used alone include: | ||
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The most common side effects of OPDIVO when used in combination with ipilimumab include:
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The most common side effects of OPDIVO when used in combination with chemotherapy include:
· pain in muscles, bones and joints
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The most common side effects of OPDIVO when used in combination with ipilimumab and chemotherapy include:
· feeling tired · pain in muscles, bones, and joints · nausea · diarrhea | · rash · decreased appetite · constipation · itching |
The most common side effects of OPDIVO when used in combination with cabozantinib include:
· diarrhea · feeling tired or weak · liver problems. See “4. Possible side effects.” · rash, redness, pain, swelling or blisters on the palms of your hands or soles of your feet · mouth sores · rash | · high blood pressure · low thyroid hormone levels · pain in muscles, bones, and joints · decreased appetite · nausea · change in the sense of taste · stomach-area (abdominal) pain · cough · upper respiratory tract infection |
The most common side effects of OPDIVO when used in combination with fluoropyrimidine and platinum-containing chemotherapy include:
· nausea · numbness, pain, tingling, or burning in your hands or feet · decreased appetite · feeling tired
| · constipation · mouth sores · diarrhea · vomiting · stomach-area (abdominal) pain · pain in muscles, bones, and joints |
These are not all the possible side effects of OPDIVO.
Call your doctor for medical advice about side effects. You may report side effects to SFDA.
General information about the safe and effective use of OPDIVO:
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet.. You can ask your healthcare provider for information about OPDIVO that is written for health professionals.
Like all medicines, this medicine can cause side effects, although not everybody gets them. Your doctor will discuss these with you and will explain the risks and benefits of your treatment.
Be aware of important symptoms of inflammation. OPDIVO acts on your immune system and may cause inflammation in parts of your body. Inflammation may cause serious damage to your body and some inflammatory conditions may be life-threatening and need treatment or withdrawal of OPDIVO.
The following side effects have been reported with OPDIVO alone:
Very common (may affect more than 1 in 10 people)
· Infections of the upper respiratory tract
· A decreased number of red blood cells (which carry oxygen), white blood cells (which are important in fighting infection) or platelets (cells which help the blood to clot)
· Decreased appetite, high sugar levels in the blood (hyperglycemia)
· Headache
· Shortness of breath (dyspnea), cough
· Diarrhea (watery, loose or soft stools), vomiting, nausea, stomach pain, constipation
· Skin rash sometimes with blisters, itching
· Pain in the muscles, bones (musculoskeletal pain) and joints (arthralgia)
· Feeling tired or weak, fever
Common (may affect up to 1 in 10 people)
· Serious lung infection (pneumonia), bronchitis
· Reactions related to the infusion of the medicine, allergic reaction (including life-threatening allergic reaction)
· Underactive thyroid gland (which can cause tiredness or weight gain), overactive thyroid gland (which can cause rapid heart rate, sweating and weight loss), swelling of the thyroid gland
· Dehydration, decrease in body weight, low sugar levels in the blood (hypoglycemia)
· Inflammation of the nerves (causing numbness, weakness, tingling or burning pain of the arms and legs), dizziness
· Blurred vision, dry eyes
· Fast heart rate, abnormal heart rhythm
· High blood pressure (hypertension)
· Inflammation of the lungs (pneumonitis, characterized by coughing and difficulty breathing), fluid around the lungs
· Inflammation of the intestines (colitis), mouth ulcers and cold sores (stomatitis), dry mouth
· Skin color change in patches (vitiligo), dry skin, redness of the skin, unusual hair loss or thinning
· Inflammation of the joints (arthritis)
· Kidney failure (including abrupt loss of kidney function)
· Pain, chest pain, edema (swelling)
Uncommon (may affect up to 1 in 100 people)
· Increase in some white blood cells
· Chronic diseases associated with a build‑up of inflammatory cells in various organs and tissues, most commonly the lungs (sarcoidosis)
· Decreased secretion of hormones produced by adrenal glands (glands situated above the kidneys), underactive function (hypopituitarism) or inflammation (hypophysitis) of the pituitary gland situated at the base of the brain, diabetes
· Increased acid levels in the blood (metabolic acidosis)
· Damage to nerves causing numbness and weakness (polyneuropathy), inflammation of the nerves caused by the body attacking itself, causing numbness, weakness, tingling or burning pain (autoimmune neuropathy)
· Inflammation of the eye (which causes pain and redness)
· Inflammation of the heart muscle, inflammation of the covering of the heart and accumulation of fluid around the heart (pericardial disorders), changes in the rhythm or rate of the heartbeat
· Fluid in the lungs
· Inflammation of the pancreas (pancreatitis), inflammation of the stomach (gastritis)
· Inflammation of the liver (hepatitis), blockage of bile ducts (cholestasis)
· Skin disease with thickened patches of red skin, often with silvery scales (psoriasis), skin condition of the face where the nose and cheeks are unusually red (rosacea), severe condition of the skin that causes red, often itchy spots, similar to the rash of measles, which starts on the limbs and sometimes on the face and the rest of the body (erythema multiforme), hives (itchy, bumpy rash)
· Inflammation of the muscles causing pain or stiffness (polymyalgia rheumatica)
Rare (may affect up to 1 in 1000 people)
· A temporary and reversible non‑infectious inflammation of the protective membranes surrounding the brain and spinal cord (aseptic meningitis)
· A disease causing the inflammation or enlargement of a lymph node (Kikuchi lymphadenitis)
· Acid in the blood produced from diabetes (diabetic ketoacidosis), decreased function of the parathyroid gland
· A temporary inflammation of the nerves that causes pain, weakness, and paralysis in the extremities (Guillain-Barré syndrome), loss of the protective sheath around nerves (demyelination), a condition in which the muscles become weak and tire easily (myasthenic syndrome), inflammation of the brain
· Inflammatory disease of blood vessels
· Ulcer of the small intestines
· Severe and possibly fatal peeling of the skin (toxic epidermal necrolysis or Stevens-Johnson syndrome)
· Disease in which the immune system attacks the glands that make moisture for the body, such as tears and saliva (Sjogren’s syndrome), aching muscles, muscle tenderness or weakness, not caused by exercise (myopathy), inflammation of the muscles (myositis), stiffness in muscles and joints, muscle spasm (rhabdomyolysis)
· Inflammation of the kidney, inflammation of the bladder, signs and symptoms may include frequent and/or painful urination, urge to pass urine, blood in urine, pain or pressure in lower abdomen
Other side effects that have been reported with frequency not known (cannot be estimated from the available data):
· A condition where the immune system makes too many infection-fighting cells called histiocytes and lymphocytes that may cause various symptoms (called hemophagocytic lymphohistiocytosis)
· Solid organ transplant rejection
· A group of metabolic complications occurring after cancer treatment characterized by high blood levels of potassium and phosphate, and low blood levels of calcium (tumor lysis syndrome)
· An inflammatory disorder (most likely of autoimmune origin) affecting the eyes, skin and the membranes of the ears, brain and spinal cord (Vogt-Koyanagi-Harada syndrome)
· Pain, numbness, tingling, or weakness in the arms or legs; bladder or bowel problems including needing to urinate more frequently, urinary incontinence, difficulty urinating and constipation (myelitis/transverse myelitis)
· Changes in any area of the skin and/or genital area that are associated with drying out, thinning, itching and pain (lichen sclerosus or other lichen disorders)
The following side effects have been reported with OPDIVO in combination with other anti-cancer medicines (the frequency and severity of side effects may vary with the combination of anti-cancer medicines received):
Very common (may affect more than 1 in 10 people)
· Infections of the upper respiratory tract
· A decreased number of red blood cells (which carry oxygen), white blood cells (which are important in fighting infection) or platelets (cells which help the blood to clot)
· Underactive thyroid gland (which can cause tiredness or weight gain), overactive thyroid gland (which can cause rapid heart rate, sweating and weight loss)
· Decreased appetite, decrease in body weight, decreased levels of albumin in the blood, high (hyperglycemia) or low (hypoglycemia) sugar levels in the blood
· Inflammation of the nerves (causing numbness, weakness, tingling or burning pain of the arms and legs), headache, dizziness, altered sense of taste
· High blood pressure (hypertension)
· Shortness of breath (dyspnea), cough, abnormal speaking sound (dysphonia)
· Diarrhea (watery, loose or soft stools), constipation, vomiting, nausea, stomach pain, mouth ulcers and cold sores (stomatitis), indigestion (dyspepsia)
· Skin rash sometimes with blisters, itching, pain of the hands or soles of the feet: rash or redness of the skin, tingling and tenderness developing to symmetrical redness, swelling and pain primarily on the palm of the hand and sole of the foot (palmar-plantar erythrodysesthesia syndrome)
· Pain in the joints (arthralgia), pain in the muscles and bones (musculoskeletal pain), muscle spasm
· Excess protein in urine
· Feeling tired or weak, fever, edema (swelling)
Common (may affect up to 1 in 10 people)
· Serious lung infection (pneumonia), bronchitis, inflammation of the eye (conjunctivitis)
· Increase in some white blood cells, decrease in neutrophils with fever
· Allergic reaction, reactions related to the infusion of the medicine
· Decreased secretion of hormones produced by adrenal glands (glands situated above the kidneys), underactive function (hypopituitarism) or inflammation (hypophysitis) of the pituitary gland situated at the base of the brain, swelling of the thyroid gland, diabetes
· Dehydration, decreased levels of phosphate in the blood
· Sensations like numbness and tingling (paresthesia)
· Hearing a persistent sound in your ear when no sound exists (tinnitus)
· Blurred vision, dry eye
· Fast heart rate, abnormal heart rhythm, inflammatory disease of blood vessels
· Formation of a blood clot within a blood vessel (thrombosis)
· Inflammation of the lungs (pneumonitis, characterized by coughing and difficulty breathing), fluid around the lungs, blood clots, nose bleeding
· Inflammation of the intestines (colitis), inflammation of the pancreas (pancreatitis), dry mouth, inflammation of the stomach (gastritis), oral pain, hemorrhoids (piles)
· Inflammation of the liver
· Skin color change in patches (including vitiligo), redness of the skin, unusual hair loss or thinning, hair color change, hives (itchy rash), discoloration or abnormal darkening of the skin (skin hyperpigmentation), dry skin
· Inflammation of the joints (arthritis), muscle weakness, aching muscles
· Kidney failure (including abrupt loss of kidney function)
· Pain, chest pain, chills
· Feeling generally unwell (malaise)
Uncommon (may affect up to 1 in 100 people)
· Acid in the blood produced from diabetes (diabetic ketoacidosis)
· Increased acid levels in the blood
· A temporary inflammation of the nerves that causes pain, weakness and paralysis in the extremities (Guillain-Barré syndrome); damage to nerves causing numbness and weakness (polyneuropathy); foot drop (peroneal nerve palsy); inflammation of the nerves caused by the body attacking itself, causing numbness, weakness, tingling or burning pain (autoimmune neuropathy); muscle weakness and tiredness without atrophy (myasthenia gravis or syndrome)
· Inflammation of the brain
· Inflammation of the eye (which causes pain and redness)
· Changes in the rhythm or rate of the heartbeat, slow heart rate, inflammation of the heart muscle
· Intestinal perforation, inflammation of the duodenum, burning or painful sensation in the tongue (glossodynia)
· Severe and possibly fatal peeling of the skin (Stevens-Johnson syndrome), skin disease with thickened patches of red skin, often with silvery scales (psoriasis), severe condition of the skin that causes red, often itchy spots, similar to the rash of measles, which starts on the limbs and sometimes on the face and the rest of the body (erythema multiforme)
· Muscle tenderness or weakness, not caused by exercise (myopathy), inflammation of the muscles (myositis), stiffness in muscles and joints, inflammation of the muscles causing pain or stiffness (polymyalgia rheumatica), bone damage in the jaw, abnormal opening between two body parts, such as an organ or blood vessel and another structure (fistula)
· Inflammation of the kidney, inflammation of the bladder, signs and symptoms may include frequent and/or painful urination, urge to pass urine, blood in urine, pain or pressure in lower abdomen
Rare (may affect up to 1 in 1000 people)
· Temporary and reversible non-infectious inflammation of the protective membranes surrounding the brain and spinal cord (aseptic meningitis)
· Chronic diseases associated with a build-up of inflammatory cells in various organs and tissues, most commonly the lungs (sarcoidosis)
· Decreased function of the parathyroid gland
· A group of metabolic complications occurring after cancer treatment characterized by high blood levels of potassium and phosphate, and low blood levels of calcium (tumor lysis syndrome)
· An inflammatory disorder (most likely of autoimmune origin) affecting the eyes, skin and the membranes of the ears, brain and spinal cord (Vogt-Koyanagi-Harada syndrome)
· Inflammation of the nerves
· Pain, numbness, tingling, or weakness in the arms or legs; bladder or bowel problems including needing to urinate more frequently, urinary incontinence, difficulty urinating and constipation (myelitis/transverse myelitis)
· Severe and possibly fatal peeling of the skin (toxic epidermal necrolysis), changes in any area of the skin and/or genital area that are associated with drying out, thinning, itching and pain (lichen sclerosus or other lichen disorders)
· Chronic disease of joints (spondyloarthropathy), disease in which the immune system attacks the glands that make moisture for the body, such as tears and saliva (Sjogren’s syndrome), muscle spasm (rhabdomyolysis)
Other side effects that have been reported with frequency not known (cannot be estimated from the available data):
· A condition where the immune system makes too many infection-fighting cells called histiocytes and lymphocytes that may cause various symptoms (called hemophagocytic lymphohistiocytosis)
· Solid organ transplant rejection
· Inflammation of the covering of the heart and accumulation of fluid around the heart (pericardial disorders)
Tell your doctor immediately if you get any of the side effects listed above. Do not try to treat your symptoms with other medicines on your own.
Changes in test results
OPDIVO alone or in combination may cause changes in the results of tests carried out by your doctor. These include:
· Abnormal liver function tests (increased amounts of the liver enzymes aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, or alkaline phosphatase in your blood, higher blood levels of the waste product bilirubin)
· Abnormal kidney function tests (increased amounts of creatinine in your blood)
· An increased level of the enzyme that breaks down fats and of the enzyme that breaks down starch
· Increased or decreased amount of calcium or potassium
· Increased or decreased blood levels of magnesium or sodium
· Increased amount of thyroid stimulating hormone
· Increase in blood triglyceride levels in the blood
· Increase in cholesterol levels in the blood
5. How to store OPDIVO
Keep out of the reach and sight of children.
Store OPDIVO under refrigeration at 2°C to 8°C. Protect OPDIVO from light by storing in the original package until time of use. Do not freeze or shake.
6. Further information
What OPDIVO contains:
· Active ingredient: nivolumab
· Inactive ingredients: mannitol, pentetic acid, polysorbate 80, sodium chloride, sodium citrate dihydrate, and Water for Injection. May contain hydrochloric acid and/or sodium hydroxide.
c. Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder
Bristol-Myers Squibb Company
Princeton, New Jersey 08543 USA
Manufactured by:
Bristol-Myers Squibb Holdings Pharma, Ltd. Liability Company
Bo. Tierras Nuevas, Road 686, Km 2.3
Manati, Puerto Rico 00674 USA
. ما هو أوبديفو وما هي دواعي استخدامه
أوبديفو دواء يصرف بوصفة طبية يستخدم في علاج:
· البالغين والأطفال الذين أعمارهم 12 سنة فما فوق والمصابين بنوع من سرطان الجلد يدعى الميلانوما.
o يمكن استخدام أوبديفو وحده أو إلى جانب إيبيليموماب لعلاج الميلانوما الذي تفشى أو يتعذر إزالته جراحياً (ميلانوما متقدمة)، أو
o يمكن استخدام أوبديفو وحده للمساعدة على منع معاودة الإصابة بالميلانوما المرحلة IIB، أو المرحلة IIC، أو المرحلة III أو المرحلة IV بعد إزالته بالكامل جراحياً.
· البالغين المصابين بسرطان الرئة غير صغير الخلايا المتقدم (أحد أنواع سرطان الرئة) قبل الاستئصال لدى البالغين (علاج سابق للجراحة يطلق عليه العلاج المساعد الجديد)
· البالغين المصابين بنوع من سرطان الرئة يدعى بسرطان الرئة غير صغيرة الخلايا (NSCLC).
o يمكن استخدام أوبديفو إلى جانب إيبيليموماب ودروتين من العلاج الكيميائي الذي يحتوي بلاتين وعلاج كيميائي آخر، كعلاج أول لسرطان الرئة غير صغير الخلايا عندما يكون سرطان الرئة:
§ انتشاره أو نموه أو عودته،
§ ولم يكن بالأورام جين متلقي عامل النمو البشروي (EGFR) أو كيناز اللمفومة الكشمي (ALK) غير طبيعي.
o قد يستخدم أوبديفو عند الإصابة بسرطان الرئة في حالة:
§ انتشاره أو نموه
§ وبعد تجربة العلاج الكيميائي الذي يحتوي على البلاتين، ولم يحدث التأثير المطلوب أو لم يعد مؤثراً.
§ إذا كان الورم به جين متلقي عامل النمو البشروي (EGFR) أو كيناز اللمفومة الكشمي (ALK) غير طبيعي، كما يجب أن تكون جربت علاجاً معتمداً للأورام بهذه الجينات غير الطبيعية، ولم يحدث التأثير المطلوب أو لم يعد مؤثراً.
· المرضى البالغين المصابين بنوع من السرطان يؤثر على بطانة الرئتين وجدار الصدر ويُطلَق عليه سرطان الغشاء البلوري المحيط بالرئتين.
o يمكن استخدام أوبديفو إلى جانب إيبيليموماب باعتباره علاجاً أولياً لسرطان الغشاء البلوري المحيط بالرئتين الذي يتعذر استئصاله جراحياً.
· البالغين المصابين بسرطان الكلية (سرطانة الخلية الكلوية).
o يمكن استخدام أوبديفو إلى جانب إيبيليموماب لعلاج بعض حالات البالغين عند انتشار السرطان (سرطانة الخلية الكلوية المتقدمة)، ولم تتلقى بالفعل العلاج لسرطانة الخلية الكلوية المتقدمة.
o يمكن استخدام أويديفو إلى جانب كابوزانتينب عند انتشار السرطان (سرطانة الخلية الكلوية المتقدمة)، ولم تتلقى بالفعل العلاج لسرطانة الخلية الكلوية المتقدمة.
o يمكن استخدام أوبديفو وحده لعلاج السرطان الذي انتشر أو نمى بعد العلاج بأدوية علاج السرطان الأخرى.
· البالغون المصابون بنوع من سرطان الدم يدعى لمفومة هودجكين الكلاسيكية.
o يمكن استخدام أوبديفو في حالة:
§ عودة السرطان أو انتشاره بعد الخضوع لأحد أنواع زراعة الخلايا الجذعية التي تستخدم خلاياك الجذعية (الخلايا الذاتية)،
§ واستخدام دواء برنتوكسيماب فيدوتين قبل أو بعد زرع الخلايا الجذعية، أو
§ تلقي على الأقل 3 أنواع من العلاج، من بينهم زرع الخلايا الجذعية التي يُستخدم بها خلايا جذعية من المريض نفسه (ذاتية المنشأ).
· البالغين المصابين بسرطان الراس والعنق (سرطانة الخلية الحرشفية).
o يمكن استخدام أوبديفو لعلاج سرطان الرأس والعنق في حالة:
§ معاودة الإصابة بالسرطان أو انتشاره،
§ وبعد تجربة العلاج الكيميائي الذي يحتوي على البلاتين، ولم يحدث التأثير المطلوب أو لم يعد مؤثراً.
· البالغين المصابين بسرطان بجدار المسالك البولية (سرطانة الظهارة البولية).
o يمكن استخدام أوبديفو للمساعدة على منع معاودة الإصابة بسرطان المسالك البولية بعد إزالته جراحياً.
o قد يُستخدم أوبديفو إلى جانب أدوية العلاج الكيميائي سيسبلاتين وجيمسيتابين كالعلاج الأول لك عند انتشار سرطان المسالك البولية (نقيلي) أو عندما يتعذر إزالته جراحياً.
- يمكن استخدام أوبديفو عند انتشار أو نمو سرطان المسالك البولية (متقدم موضعياً أو نقيلي)،
§ وبعد تجربة العلاج الكيميائي الذي يحتوي على البلاتين، ولم يحدث التأثير المطلوب أو لم يعد مؤثراً، أو
§ أصبح السرطان أسوأ خلال 12 شهراً بالعلاج الكيميائي الذي يحتوي البلاتين، إم قبل أو بعد إزالة السرطان جراحياً.
· البالغين المصابين بسرطان الأنبوب الذي يربط بين الحلق والمعدة (سرطان المريء).
o يمكن استخدام أوبديفو لمنع معاودة الإصابة بسرطان المريء أو الموصل المعدي المريئي في حالة:
§ علاج سرطان المريء أو الموصل المعدي المريئي بعلاج كيميائي إشعاعي تتبعه الجراحة لإزالته تماماً، لكن
§ لا تزال هناك بعض خلايا السرطان في العقد الليمفاوية أو الورم الذي تمت إزالته.
o يمكن استخدام أوبديفو إلى جانب علاج كيميائي يحتوي فلوروبيريميدين وبلاتين عندما يكون سرطان المريء:
§ إذا كان سرطان المريء من نوع يُطلق عليه سرطان الخلايا الحرشفية،
§ ولا يمكن إزالته جراحياً (متقدم)، أو إذا انتشر إلى أجزاء أخرى من الجسم (نقيلي)،
§ ولم تتلقَ بالفعل العلاج لسرطان المريء المتقدم أو النقيلي.
o يمكن استخدام أوبديفو إلى جانب إيبيليموماب في الحالات التالية:
§ إذا كان سرطان المريء من نوع يُطلق عليه سرطان الخلايا الحرشفية،
§ ولا يمكن إزالته جراحياً (متقدم)، أو إذا انتشر إلى أجزاء أخرى من الجسم (نقيلي)،
§ ولم تتلقَ بالفعل العلاج لسرطان المريء المتقدم أو النقيلي.
o يمكن استخدام أوبديفو وحده لعلاج سرطان المريء في الحالات التالية:
§ إذا كان سرطان المريء من نوع يُطلق عليه سرطان الخلايا الحرشفية،
§ ولا يمكن استئصاله جراحيًا،
§ إذا عاد سرطان المريء أو انتشر في أجزاء أخرى من الجسم بعد تلقي العلاج الكيماوي الذي يحتوي على فلوروبيريميدين وبلاتين.
· البالغين المصابين بسرطان المعدة، بسرطان بموضع اتصال المريء بالمعدة (سرطان الموصل المعدي المريئي، والبالغين المصابين بسرطانة غدية مريئية.
o يمكن استخدام أوبديفو إلى جانب علاج كيميائي يحتوي فلوروبيريميدين وبلاتين عندما يكون سرطان المعدة، أو الموصل المعدي المريئي، أو سرطان المريء:
§ لا يمكن استئصاله جراحيًا، أو
§ إذا انتشر إلى أجزاء أخرى من الجسم.
لا يُعرف إذا ما كان أوبديفو آمناً وفعالاً:
· للأطفال أقل من 12 عاماً المصابين بالميلانوما.
· من غير المعروف ما إذا كان أوبديفو آمناً وفعالاً في الأطفال لعلاج أي أنواع أخرى من السرطان.
2. قبل استخدام أوبديفو
يجب ألا تستخدم أوبديفو
• إذا كنت تعاني من الحساسية تجاه نيفولوماب أو أي من المكونات الأخرى لهذا الدواء (المذكورة في القسم 6 "معلومات إضافية"). تحدث مع طبيبك إذا لم تكن متأكداً.
تحذيرات واحتياطات
أخبر مقدم الرعاية الصحية بجميع حالاتك الصحية، وذلك يشمل:
· إذا كنت مصاباً بمشكلات في الجهاز المناعي مثل مرض كرون، أو التهاب القولون التقرحي، أو الذئبة
· إذا خضعت من قبل لعملية زرع أعضاء
· إذا خضعت أو تخطط للخضوع لزرع خلايا جذعية استخدم بها خلايا جذعية من متبرع (خيفي)
· إذا سبق أن تلقيت علاجاً إشعاعياً لمنطقة الصدر وتلقيت أدوية أخرى مثل أوبديفو
· إذا كنت مصاباً بحالة تؤثر على الجهاز العصبي، مثل الوهن العضلي الوبيل او متلازمة غيلان باريه
يُرجى المراجعة مع الطبيب أو الممرضة قبل استخدام أوبديفو في الحالات التالية:
• إذا كنت مصاباً بأحد أمراض المناعة الذاتية (حالة يهاجم فيها الجسم خلاياه)؛
• إذا كنت مصاباً بميلانوما العين؛
• إذا كنت سبق أن حصلت على إيبيليموماب، أو دواء آخر لعلاج الميلانوما، وعانيت من آثار جانبية خطيرة بسبب ذلك الدواء؛
• إذا كنت قد عرفت أن السرطان لديك انتشر إلى المخ؛
• إذا كان لديك أي تاريخ لالتهاب الرئتين؛
• إذا كنت تتناول أدوية لتثبيط جهازك المناعي.
مضاعفات زراعة الخلايا الجذعية التي تستخدم الخلايا الجذعية للمتبرع (خيفية) بعد العلاج باستخدام أوبديفو. قد تكون هذه المضاعفات خطيرة وقد تؤدي إلى الوفاة. سيراقبك مقدم الرعاية الصحية للتأكد من عدم وجود أي علامات على المضاعفات إذا كنت خضعت لزراعة الخلايا الجذعية الخيفية.
أخبر مقدم الرعاية الصحية بجميع الأدوية التي تتناولها، بما في ذلك جميع الأدوية التي تُصرف بوصفة طبية والتي تُصرف بدونها،
والفيتامينات، والمكملات العشبية.
تحدث إلى طبيبك قبل استخدام أوبديفو حيث أنه قد يسبب:
· مشكلات قلبية مثل تغير نظم القلب أو معدل ضربات القلب أو عدم انتظام نظم القلب.
· مشكلات رئوية كصعوبة التنفس أو السعال. وقد تكون هذه علامات على التهاب الرئتين (الالتهاب الرئوي أو مرض الرئة الخلالي).
· الإسهال (براز سائل أو لين) أو أي من أعراض التهاب الأمعاء (التهاب القولون)، مثل ألم البطن ووجود مخاط أو دم في البراز.
· التهاب الكبد. ويمكن أن تتضمن علامات وأعراض التهاب الكبد نتائج غير طبيعية لاختبارات وظائف الكبد أو اصفرار العينين أو الجلد (اليرقان) أو ألم الجانب الأيمن من منطقة البطن أو التعب.
· التهاب أو مشكلات في الكلى. ويمكن أن تتضمن العلامات والأعراض نتائج غير طبيعية لاختبارات وظائف الكلى أو نقص كمية البول.
· مشكلات الغدد المنتجة للهرمونات (بما في ذلك الغدد النخامية والدرقية والجار درقية والكظرية) التي قد تؤثر على كيفية عمل هذه الغدد. وقد تتضمن أعراض وعلامات عدم عمل هذه الغدد جيداً الإجهاد (التعب الشديد) أو تغير الوزن أو الصداع، أو اتخفاض مستويات كالسيوم الدم والاضطرابات البصرية.
· مرض السكري الذي يتضمن مشكلة خطيرة، وفي بعض الأحيان مهددة للحياة، نظراً لوجود الحمض في الدم نتيجة للإصابة بمرض السكري (الحماض الكيتوني السكري). قد تتضمن الأعراض الشعور بالجوع أوالعطش أكثر من المعتاد، أو الحاجة للتبول لعدد مرات أكثر، أو انخفاض الوزن، أو الشعور بالأجهاد أو صعوبة التفكير بوضوح، أو نفس برائحة حلوة أو رائحة الفاكهة، أو مذاق حلو أو معدني في الفم، أو بول أو عرق برائحة مختلفة، أو الشعور بالغثيان أو القيء، وألم المعدة، وعمق أو تسارع النفس.
· التهاب الجلد الذي يمكن أن يسبب تفاعلات جلدية حادة (يُعرف باسم تقشر الأنسجة المتموتة البشروية التسممي ومتلازمة ستيفنز جونسون). ويمكن أن تتضمن علامات وأعراض التفاعلات الجلدية الحادة الطفح الجلدي والحكة وتقشر الجلد (الذي قد يؤدي إلى الوفاة).
· التهاب العضلات مثل التهاب عضلة القلب والتهاب العضلات وانحلال الربيدات (تيبس في العضلات والمفاصل وتشنج العضلات). ويمكن أن تتضمن العلامات والأعراض ألم وتيبس وضعف العضلات أو ألم الصدر أو الإجهاد الشديد.
· رفض زراعة الأعضاء الصلبة.
· داء الطعم حيال المضيف.
· داء البلعمة. مرض نادر يقوم به الجهاز المناعي بإنتاج كمية أكبر من المعتاد من الخلايا المقاومة للعدوى الطبيعية تسمى المنسجات والخلايا اللمفاوية. قد تتضمن الأعراض تضخم الكبد و/أو الطحال والطفح الجلدي وتضخم العقد اللمفاوية ومشكلات التنفس وسهولة التكدم والاضطرابات الكلوية والمشكلات القلبية.
أخبر طبيبك على الفور إذا ظهرت عليك أي من هذه الأعراض أو في حالة تفاقمها. ولا تحاول علاج الأعراض التي تظهر عليك بنفسك باستخدام أدوية أخرى. فقد يقوم طبيبك بأي مما يلي:
· إعطائك أدوية أخرى للوقاية من المضاعفات والحد من الأعراض.
· تأجيل الجرعة التالية من أوبديفو،
· أو إيقاف علاجك بأوبديفو تماماً.
يُرجى ملاحظة أن ظهور هذه العلامات والأعراض يتأخر في بعض الأحيان، وقد تظهر بعد أسابيع أو أشهر من آخر جرعة تتلقاها. لذا سيقوم طبيبك بفحص صحتك العامة قبل البدء في العلاج. وستخضع أيضاً لإجراء اختبارات دم خلال فترة علاجك.
الأطفال والمراهقون
لا يجب استخدام أوبديفو لمعالجة الأطفال والمراهقين دون سن 18 عاماً باستثناء المراهقين البالغين 12 سنة فما فوق والمصابين بالميلانوما.
الأدوية الأخرى وأوبديفو
قبل استخدام أوبديفو، عليك إخبار طبيبك إذا كنت تستخدم أي أدوية لكبت الجهاز المناعي، مثل الستيرويدات القشرية، لأن هذه الأدوية قد تتداخل مع تأثير أوبديفو. ولكن بمجرد تلقي العلاج بأوبديفو، قد يعطيك طبيبك الستيرويدات القشرية للحد من أي آثار جانبية محتملة قد تظهر عليك أثناء فترة علاجك وهذا لن يقلل تأثير الدواء.
يُرجى إخبار طبيبك إن كنت تتناول أو تناولت مؤخراً أي أدوية أخرى. ولا تتناول أي أدوية أخرى خلال فترة العلاج بدون التحدث إلى طبيبك أولاً.
الحمل والرضاعة الطبيعية
أخبري طبيبك إذا كنتِ:
• حاملاً أو تخططين للحمل، فقد يضر أوبديفو بجنينك.
السيدات القادرات على الحمل
o يجب على مقدم الرعاية الصحية أن يجري اختباراً للحمل قبل البدء بتلقي علاج أوبديفو.
o يجب استخدام وسيلة فعالة لمنع الحمل أثناء العلاج بأوبديفو ولمدة 5 أشهر بعد الجرعة الأخيرة من هذا الدواء. تحدثي إلى مقدم
الرعاية الصحية حول وسائل منع الحمل التي يمكنك استخدامها خلال هذه الفترة.
o أخبري مقدم الرعاية الصحية على الفور إذا ما أصبحتِ حاملاً خلال العلاج بدواء أوبديفو.
• إذا كنتِ ترضعين رضاعة طبيعية أو تخططين لذلك، لا يُعرَف ما إذا كان أوبديفو يمر إلى حليب الثدي. لا ترضعي رضاعة طبيعية
أثناء العلاج بأوبديفو ولمدة 5 أشهر بعد الجرعة الأخيرة من هذا الدواء.
القيادة واستخدام الآلات
قد يحدث أوبديفو أو أوبديفو إلى جانب إيبيليموماب تأثيراً طفيفاً على القدرة على القيادة واستخدام الآلات، لكن توخ الحذر عند ممارسة هذه الأنشطة إلى أن تتأكد أن أوبديفو لا يؤثر عليك سلباً.
يحتوي أوبديفو على الصوديوم
أخبر طبيبك إذا كنت تتبع نظاماً غذائياً منخفض الصوديوم (قليل الأملاح) قبل استخدام أوبديفو، فهذا الدواء يحتوي على 2.5 ملغ من الصوديوم (المكون الرئيسي لملح الطعام) لكل مل من المركز.
يحتوي أوبديفو 10 ملغ صوديوم في كل 4 قارورة 4 مل أو 25 ملغ صوديوم في كل قارورة 10 مل، مما يعادل 0.5% أو 1.25% على التوالي، من الحد الأقصى للمدخول الغذائي اليومي الموصى به من الصوديوم لشخص بالغ.
ستجد معلومات رئيسية من نشرة العبوة هذه في بطاقة تنبيه المريض الذي يعطيها الطبيب لك والتي يجب عليك الاحتفاظ بها وإطلاع زوجتك أو مقدم الرعاية عليها.
3. كيفية استخدام أوبديفو
· سيقدم لك مقدم الرعاية الصحية أوبديفو بالحقن الوريدي من خلال أنبوبة وريدية (IV) على مدار 30 دقيقة.
· عند استخدام أوبديفو وحده، عادة ما يقدم كل أسبوعين أو 4 أسابيع بحسب الجرعة التي تتلقاها.
· عند استخدام أوبديفو إلى جانب إيبيليموماب (فيما عدا لعلاج سرطان الرئة غير صغير الخلايا)، عادة ما يقدم أوبديفو كل 3 أسابيع بإجمالي 4 جرعات. ويُعطى إيبيليموماب في اليوم نفسه. بعد ذلك، يُعطى أوبديفو وحده كل أسبوعين أو 4 أسابيع بحسب الجرعة التي تتلقاها.
· في حالة سرطان الرئة غير صغير الخلايا (NSCLC) قبل إجراء الجراحة، يُعطى أوبديفو بالتزامن مع العلاج الكيميائي كل 3 أسابيع على مدى 3 دورات.
· لعلاج سرطان الرئة غير صغير الخلايا (NSCLC) الذي انتشر إلى أجزاء أخرى من الجسم، عند استخدام أوبديفو إلى جانب إيبيليموماب، يقدم أوبديفو كل 3 أسابيع، ويقدم إيبيليموماب كل 6 أسابيع حتى عامين. سيحدد مقدم الرعاية الصحية عدد مرات العلاج التي تحتاجها.
· لعلاج سرطان الغشاء البلوري المحيط بالرئتين الخبيث، يُقدم أوبديفو كل 3 أسابيع ويُعطى إيبيليموماب كل 6 أسابيع لفترة تصل إلى عامين.
· لسرطانة الخلية الكلوية، عند استخدامه إلى جانب كابوزانتينب، يقدم أوبديفو عادة كل أسبوعين أو 4 أسابيع، بحسب الجرعة التي تتلقاها. ويقدم كابوزانتينب مرة واحدة يومياً عن طريق الفم.
· بالنسبة لسرطان الظهارة البولية الذي انتشر إلى أجزاء أخرى من جسمك أو لا يمكن إزالته جراحياً، عند استخدام أوبديفو إلى جانب أدوية العلاج الكيميائي سيسبلاتين وجيمسيتابين، فإن أوبديفو يُعطى كل 3 أسابيع لمدة تصل إلى 6 دورات. وسيُعطى العلاج الكيميائي في نفس اليوم. وبعد ذلك، سيُعطى أوبديفو وحده كل أسبوعين أو 4 أسابيع حسب الجرعة التي تتلقاها.
· عند استخدام أوبديفو مع علاج كيميائي لعلاج سرطانة الخلية الحرشفية المريئية (ESCC)، يقدم أوبديفوا إما كل أسبوعين أو 4 أسابيع، لمدة تصل إلى عامين.
· عند استخدام أوبديفو إلى جانب إيبيليموماب لعلاج سرطانة الخلية الحرشفية المريئية، يقدم أوبديفو كل أسبوعين أو 3 أسابيع ويقدم إيبيليموماب كل 6 أسابيع لمدة تصل إلى عامين.
· لسرطان المعدة، وسرطان الموصل المعدي المريئي، وسرطانة غدية مريئية، عند استخدام إلى جانب علاج كيميائي يحتوي فلوروبيريميدين وبلاتين، يقدم أوبديفو كل أسبوعين أو 3 أسابيه بحسب الجرعة التي تتلقاها، لمدة تصل إلى عامين, ويقدم العلاج الكيميائي في اليوم نفسه.
· يقرر مقدم الرعاية الصحية عدد مرات العلاج التي تحتاجها.
· سيجري مقدم الرعاية الصحية اختبارات للدم لرصد الآثار الجانبية.
· إذا فوّت أي مواعيد، اطلب من مقدم الرعاية الصحية تحديد موعد جديد لك في أقرب وقت ممكن.
4. الآثار الجانبية المحتملة
أوبديفو دواء لعلاج أنواع محددة من السرطان بالعمل مع جهاز المناعة. قد يتسبب أويديفو في مهاجمة جهاز المناعة لأعضاء وأنسجة طبيعية في أي منطقة بالجسم وقد يؤثر على طبيعة عملها. وفي بعض الأحيان، يمكن أن تصبح هذه المشكلات خطيرة أو يمكن أن تؤدي إلى الوفاة. قد تحدث هذه المشكلات بأي وقت من العلاج أو حتى بعد انتهاء فترة العلاج. ربما تعاني من أكثر من مشكلة من هذه المشكلات في الوقت نفسه. قد تحدث بعض هذه المشكلات بوتيرة أعلى عند استخدام أوبديفو إلى جانب علاج آخر.
اتصل بمقدم الرعاية الصحية أو اذهب على الفور لرؤيته إذا ظهرت عليك أي علامات أو أعراض جديدة أو أصبحت أسوأ، وذلك يشمل:
مشكلات رئوية.
· الإصابة بالسعال أو تفاقمه
· ضيق تنفس
· ألم في الصدر
مشكلات معوية.
· الإسهال (براز لين) أو زيادة حركة الأمعاء عن المعتاد
· خروج براز أسود غامق كالقطران ولزج، أو به دم أو مخاط
· آلام حادة في منطقة المعدة (البطن) أو طراوة
مشكلات كبدية.
· اصفرار الجلد أو بياض العينين
· غثيان أو قيء شديدان
· ألم بالجانب الأيمن من منطقة المعدة (البطن)
· بول داكن (بلون الشاي)
· النزيف أو التكدم بشكل أسهل من المعتاد
مشكلات في الغدد الهرمونية.
· الصداع المستمر أو غير المعتاد
· حساسية العينين للضوء
· مشكلات بالعين
· تسارع ضربات القلب
· زيادة التعرق
· إجهاد شديد
· زيادة أو فقدان الوزن
· الشعور بالجوع أو العطش بشكل أكبر من المعتاد
· زيادة التبول أكثر من المعتاد
· تساقط الشعر
· شعور بالبرد
· إمساك
· عمق الصوت
· دوار أو إغماء
· تغيرات في الحالة النفسية أو السلوك مثل انخفاض الرغبة الجنسية، أو التهيج، أو النسيان
مشكلات كلوية.
· نقص كمية البول
· دم في البول
· تورم الكاحلين
· فقدان الشهية
مشكلات جلدية.
· الطفح الجلدي
· الحكة
· ظهور بثور أو تقشر البشرة
· التهابات أو تقرحات مؤلمة في الفم أو الأنف أو الحلق أو الأعضاء التناسلية
يمكن أن تصاب الأعضاء والأنسجة الأخرى أيضاً ببعض المشكلات. هذه ليست جميع علامات وأعراض مشكلات الجهاز المناعي التي يمكن أن تحدث عند استخدام أوبديفو. اتصل بمقدم الرعاية الصحية أو زُره على الفور إذا ظهرت لديك أي علامات أو أعراض جديدة أو عند تفاقم الأعراض الموجودة بالفعل، وذلك يشمل:
· ألم الصدر أو عدم انتظام ضربات القلب أو ضيق التنفس أو تورم الكاحلين
· الارتباك أو النعاس أو مشكلات في الذاكرة أو تغيرات في الحالة المزاجية أو السلوك أو تيبس الرقبة أو مشكلات في التوازن أو الشعور بالوخز أو الخدر في الذراعين أو الساقين
· ازدواج الرؤية أو تشوش الرؤية أو الحساسية للضوء أو ألم العينين أو تغيرات في الإبصار
· ألم أو ضعف العضلات المستمر أو الشديد أو التشنجات العضلية
· انخفاض خلايا الدم البيضاء أو ظهور الكدمات
قد يساعد الحصول على المعالجة الصحية على الفور على منع تفاقم هذه المشكلات.
سيتحقق مقدم الرعاية الصحية المتابع لحالتك من حدوث أي من هذه المشاكل لك خلال العلاج أوبديفو. وقد يستخدم مقدم الرعاية الصحية أدوية الستيرويدات القشرية أو الهرمونات البديلة لمعالجتك. كما يمكن أن يحتاج مقدم الرعاية الصحية إلى تأخير العلاج بأوبديفو أو إيقافه تماماً إذا ظهرت عليك آثار جانبية خطيرة.
قد يتسبب أوبديفو في حدوث آثار جانبية خطيرة.
· تفاعلات شديدة مرتبطة بالحقن الوريدي. اخبر مقدم الرعاية الصحية أو الممرضة على الفور إذا ما ظهرت عليك هذه الأعراض خلال الحقن الوريدي بـ أوبديفو: | |
o رعشة أو ارتجاف o حكة أو طفح جلدي o احمرار وسخونة الوجه o ضيق التنفس أو صفير | o دوار o شعور يشبه الإغماء o حمى o ألم في الظهر أو الرقبة |
· حدوث مضاعفات لزرع الخلايا الجذعية التي استخدم بها خلايا جذعية من متبرع (خيفي). يمكن أن تكون هذه المضاعفات خطيرة وقد تؤدي إلى الوفاة. قد تحدث هذه المضاعفات إذا كنت قد خضعت لعملية زرع قبل أو بعد العلاج بأوبديفو. لذا سيقوم مقدم الرعاية الصحية بمراقبتك لاكتشاف أي علامات أو مضاعفات في حالة الخضوع لزراعة الخلايا الجذعية الخيفية.
تتضمن الآثار الجانبية الأكثر شيوعاً لأوبديفو عند استخدامه وحده: | ||
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تتضمن الآثار الجانبية الأكثر شيوعاً لأوبديفو عند استخدامه بالتزامن مع إيبيليموماب:
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الآثار الجانبية الأكثر شيوعاً لأوبديفو عند استخدامه إلى جانب العلاج الكيميائي تتضمن:
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الآثار الجانبية الأكثر شيوعاً لأوبديفو عند استخدامه إلى جانب إيبيليموماب والعلاج الكيميائي تتضمن:
· الشعور بالتعب · آلام العضلات والعظام والمفاصل · الغثيان · الإسهال | · الطفح الجلدي · فقدان الشهية · إمساك · الحكة |
الآثار الجانبية الأكثر شيوعاً لـ أوبديفو عند استخدامه إلى جانب كابوزانتينب تتضمن:
· الإسهال · الشعور بالتعب أو الوهن · مشكلات كبدية. "4. الآثار الجانبية المحتملة." · طفح جلدي، إحمرار، ألم، تورم أو بثور على راحتي اليد أو باطن القدمين. · تقرحات الفم · الطفح الجلدي | · ارتفاع ضغط الدم · انخفاض مستويات هرمون الدرقية · آلام العضلات والعظام والمفاصل · فقدان الشهية · الغثيان · تغير في حاسة التذوق · ألم منطقة المعدة (البطن) · كحة · عدوى الجهاز التنفسي العلوي |
الآثار الجانبية الأكثر شيوعاً لدواء أوبديفو عند استخدامه إلى جانب العلاج الكيميائي الذي يحتوي على فلوروبيريميدين وبلاتين تتضمن:
· الغثيان · الشعور بخدر أو ألم أو وخز أو حرقة في اليدين أو القدمين · فقدان الشهية · الشعور بالتعب
| · إمساك · تقرحات الفم · الإسهال · القيء · ألم منطقة المعدة (البطن) · آلام العضلات والعظام والمفاصل |
هذه ليست جميع الآثار الجانبية المحتملة لدواء أوبديفو.
اتصل بطبيبك للحصول على استشارة طبية بشأن الآثار الجانبية. ويمكنك إبلاغ الهيئة العامة للغذاء والدواء السعودية عن الآثار الجانبية.
معلومات عامة حول الاستخدام الآمن والفعال لأويديفو:
في بعض الأحيان توصف الأدوية لأغراض أخرى غير تلك الواردة في نشرة معلومات المريض. يمكنك طرح الأسئلة على مقدم الرعاية الصحية أو الصيدلي عن المعلومات الخاصة بأوبديفو المدرجة لمتخصصي الرعاية الصحية.
مثل جميع الأدوية، يمكن لهذا الدواء أن يسبب آثاراً جانبية، على الرغم من أنه ليس بالضرورة أن يعاني منها الجميع. سيناقش طبيبك معك هذه الآثار الجانبية ويشرح مخاطر وفوائد العلاج.
كن واعياً للأعراض الهامة للالتهاب. يعمل أوبديفو على جهاز المناعة وقد يتسبب بالالتهاب في أجزاء من جسمك. قد يسبب الالتهاب أضراراً خطيرة للجسم وقد تكون بعض الحالات الالتهابية مهددة للحياة وتحتاج إلى العلاج أو انسحاب أوبديفو.
وردت الآثار الجانبية التالية في التقارير لاستخدام أوبديفو وحده:
شائعة جداً (قد تؤثر على أكثر من 1 من كل 10 أشخاص)
· التهابات الجزء العلوي من الجهاز التنفسي
· انخفاض عدد خلايا الدم الحمراء (التي تحمل الأوكسجين)، وخلايا الدم البيضاء (التي تمثل أهمية في مقاومة الالتهاب)، أو الصفائح الدموية (الخلايا التي تساعد الدم على التجلط)
· فقدان الشهية، ارتفاع مستويات السكر في الدم
· صداع
· ضيق التنفس (عسر التنفس)، السعال
· الإسهال (مائي أو لين أو طري)، القيء، الغثيان، ألم بالبطن، الإمساك
· الطفح الجلدي، المصحوب ببثور في بعض الأحيان، والحكة
· ألم العضلات والعظام (الألم العضلي الهيكلي) والمفاصل (الآلام المفصلية)
· شعور بالتعب أو الضعف، حمى
شائعة (قد تؤثر على 1 من كل 10 أشخاص)
· التهاب الرئتين الشديد (الالتهاب الرئوي)، التهاب الشعب الهوائية
· ردود فعل مرتبطة بالحقن الوريدي للدواء، ردود فعل تحسسية (تتضمن ردود فعل تحسسية مهددة للحياة)
· خمول الغدة الدرقية (الذي يمكن أن يسبب التعب أو زيادة الوزن)، فرط نشاط الغدة الدرقية (الذي يمكن أن يسبب تسارع ضربات القلب والتعرق وفقدان الوزن)، تضخم الغدة الدرقية
· الجفاف، نقص وزن الجسم، انخفاض مستويات السكر في الدم
· التهاب الأعصاب (الذي يسبب الخدر أو الوهن أو النخز أو حرقة في الذراعين والساقين)، الدوار
· تشوش الرؤية، جفاف العينين
· تسارع ضربات القلب، نظم القلب غير الطبيعي
· ارتفاع ضغط الدم
· التهاب الرئتين (الالتهاب الرئوي الذي يمثل السعال وصعوبة التنفس أبرز أعراضه)، وجود سوائل حول الرئتين
· التهاب الأمعاء (التهاب القولون)، تقرحات الفم وقرح الزكام (التهاب الفم)، جفاف الفم
· تغير لون البشرة في شكل بقع (البهاق)، جفاف الجلد، احمرار الجلد، سقوط الشعر أو ترقق كثافته على نحو غير معتاد
· التهاب المفاصل
· الفشل الكلوي (بما في ذلك التوقف المفاجئ لوظائف الكلى)
· ألم، ألم الصدر، وذمة (تورم)
غير شائعة (قد تؤثر على 1 من كل 100 شخص)
· زيادة عدد بعض خلايا الدم البيضاء
· الأمراض المزمنة المرتبطة بتراكم الخلايا الالتهابية في مختلف الأعضاء والأنسجة، ولا سيما الرئتين (الساركويد)
· انخفاض إفراز الهرمونات التي تنتجها الغدد الكظرية (الغدد التي توجد أعلى الكليتين)، خمول الغدة النخامية الوظيفي (قصور النخامية) أو التهاب الغدة النخامية التي توجد أسفل الدماغ، السكري
· ارتفاع مستويات الحمض في الدم (الحماض الأيضي)
· تلف الأعصاب الذي يسبب الخدر والوهن (اعتلال الأعصاب)، التهاب الأعصاب الذي ينتج عن مهاجمة الجسم لنفسه والذي يسبب الخدر أو الوهن أو النخز أو الحرقة (اعتلال الأعصاب المناعي الذاتي)
· التهاب العين (مما قد يُسبب الألم والاحمرار)
· التهاب عضلة القلب، التهاب الطبقة الخارجية من القلب وتراكم السوائل حوله (اضطرابات تامورية)، تغيرات في النظم أو معدل ضربات القلب
· وجود سوائل في الرئتين
· التهاب البنكرياس، التهاب المعدة
· التهاب الكبد، انسداد القنوات الصفراوية (الركود الصفراوي)
· مرض جلدي مصحوب ببقع سميكة حمراء وقشور فضية (الصدفية) في أغلب الأحيان، مرض جلدي يصيب الوجه حيث يكتسب الأنف والوجنتان حمرة غير اعتيادية (العد الوردي)، مرض جلدي شديد ينتج عنه بقع حمراء وحكة، على غرار طفح الحصبة الذي يبدأ في الأطراف وعلى الوجه في بعض الأحيان وبقية أجزاء الجسم (الحمامى متعددة الأشكال)، الشرى (الطفح الجلدي المصحوب بحكة ونتوءات جلدية)
· التهاب العضلات الذي يسبب الألم أو التيبس (ألم العضلات الروماتزمي)
نادرة (قد تؤثر على 1 من كل 1000 شخص)
· التهاب غير معدِ مؤقت وقابل للعلاج في الأغشية الواقية المحيطة بالمخ والحبل الشوكي (التهاب السحايا العقيم)
· مرض يسبب التهاب أو تضخم إحدى العقد اللمفية (التهاب العقد اللمفاوية كيكوتشي)
· وجود الحمض في الدم نتيجة للإصابة بمرض السكري (الحماض الكيتوني السكري)، تدهور وظائف الغدة الجار درقية
· التهاب الأعصاب المؤقت الذي يسبب الألم والوهن وشلل الأطراف (متلازمة غيلان باريه)، فقدان الغلاف الواقي المحيط بالأعصاب (الاعتلال المزيل للميالين)، مرض يسبب ضعف ووهن العضلات بسهولة (متلازمة الوهن العضلي)، التهاب الدماغ
· التهاب الأوعية الدموية
· قرحة الأمعاء الدقيقة
· تقشر حاد بالبشرة قد يكون مميتاً (تقشر الأنسجة المتموتة البشروية التسممي أو متلازمة ستيفنز جونسون)
· مرض يسبب مهاجمة الجهاز المناعي للغدد التي تنتج رطوبة الجسم مثل الدموع واللعاب (متلازمة شوغرن)، ألم العضلات، طراوة أو وهن العضلات غير الناتجين عن ممارسة التمرينات الرياضية (الاعتلال العضلي)، التهاب العضلات، تيبس العضلات والمفاصل، تشنج العضلات (انحلال الربيدات)
· الالتهاب الكلوي
· التهاب المثانة، علامات وأعراض قد تتضمن تبول متكرر أو مؤلم، حاجة ملحة للتبول، دم في البول، ألم ضغط في البطن السفلى
آثار جانبية أخرى لا يُعرَف مدى تكرارها (لا يمكن تقدير مدى التكرار من البيانات المتوفرة):
· حالة يقوم فيها الجهاز المناعي بإنتاج كمية أكثر من الطبيعي من الخلايا المقاومة للعدوى تسمى المنسجات والخلايا اللمفاوية التي قد تسبب أعراضاً متنوعة (تسمى داء البلعمة)
· رفض زراعة الأعضاء الصلبة
· مجموعة من المضاعفات الأيضية التي تحدث بعد علاج السرطان الذي يتسم بارتفاع مستويات بوتاسيوم وفوسفات الدم، وانخفاض مستويات كاليسيوم الدم (متلازمة انحلال الورم)
· اضطراب التهابي (مرتبط أصلًا بالمناعة الذاتية) يصيب العينين والجلد وأغشية الأذنين والمخ والحبل الشوكي (متلازمة فوجت كوياناجى هارادا)
· ألم، أو تنميل، أو توخز أو ضعف في الذراعين أو القدمين؛ مشاكل في المثانة أو الأمعاء بما في ذلك الحاجة إلى التبول بشكل أكثر تكراراً، والسلس البولي، وصعوبة التبول والإمساك (التهاب النخاع/التهاب النخاع المستعرض)
· تغيرات في أي منطقة بالجلد و/أو الأعضاء التناسلية مصحوبة بجفاف وترقق وحكة وألم (الحزاز المتصلب أو غيره من اضطرابات الحزاز)
تم الإبلاغ عن الآثار الجانبية التالية عند استخدام أوبديفو بالتزامن مع أدوية علاج السرطان الأخرى (قد يختلف مدى تكرار الآثار الجانبية وشدتها حسب مجموعة أدوية علاج السرطان المستخدمة):
شائعة جداً (قد تؤثر على أكثر من 1 من كل 10 أشخاص)
· التهابات الجزء العلوي من الجهاز التنفسي
· انخفاض عدد خلايا الدم الحمراء (التي تحمل الأوكسجين)، وخلايا الدم البيضاء (التي تمثل أهمية في مقاومة الالتهاب)، أو الصفائح الدموية (الخلايا التي تساعد الدم على التجلط)
· خمول الغدة الدرقية (الذي يمكن أن يسبب التعب أو زيادة الوزن)، فرط نشاط الغدة الدرقية (الذي يمكن أن يسبب تسارع ضربات القلب والتعرق وفقدان الوزن)
· انخفاض الشهية، انخفاض وزن الجسم، انخفاض مستويات الألبومين في الدم، ارتفاع أو انخفاض مستويات السكر في الدم
· التهاب الأعصاب (الذي يسبب الخدر أو الوهن أو النخز أو حرقة في الذراعين والساقين)، الصداع، الدوار، تغير في حاسة التذوق
· ارتفاع ضغط الدم
· ضيق التنفس (عسر التنفس)، السعال، خلل في الصوت عند التحدث (خلل النطق)
· الإسهال (براز سائل أو لين)، الإمساك، القيء، الغثيان، ألم البطن، قرح الفم وقرح الزكام (التهاب الفم)، عسر الهضم
· طفح جلدي مصحوب أحيانًا ببثور وحكة وألم في اليدين أو باطني القدمين، الطفح الجلدي أو احمرار الجلد، وخز وطراوة تتطور إلى احمرار موحد، تورم وألم في راحة اليد وباطن القدم تحديداً (متلازمة ضعف الحس الاحمراري لليدين والقدمين)
· ألم المفاصل (الألم المفصلي)، ألم العضلات والعظام (الألم العضلي الهيكلي)، التقلصات العضلية
· زيادة البروتين في البول
· شعور بالتعب أو الضعف، حمى، وذمة (تورم)
شائعة (قد تؤثر على 1 من كل 10 أشخاص)
· التهاب الرئتين الشديد (الالتهاب الرئوي)، التهاب الشعب الهوائية، التهاب العينين (التهاب الملتحمة)
· زيادة بعض خلايا الدم البيضاء، نقص العدلات مع الحمى
· ردود الفعل التحسسية، ردود الفعل المرتبطة بالحقن الوريدي للدواء
· انخفاض إفراز الهرمونات التي تنتجها الغدد الكظرية (الغدد التي توجد أعلى الكليتين)، خمول الغدة النخامية الوظيفي (قصور النخامية) أو التهاب الغدة النخامية التي توجد أسفل الدماغ، تورم الغدة الدرقية، السكري
· الجفاف، انخفاض مستويات الفوسفات في الدم
· الشعور بالخدر والوخز (المذل)
· سماع صوت مستمر في الأذنين في حالة عدم وجود صوت (الطنين)
· تشوش بالرؤية، جفاف العين
· سرعة معدل ضربات القلب، اضطرابات إيقاع القلب، التهاب الأوعية الدموية
· تكون جلطة دموية في أحد الأوعية الدموية (تخثر الدم)
· التهاب الرئتين (الالتهاب الرئوي الذي يمثال السعال وصعوبة التنفس)، وجود سوائل حول الرئتين، الجلطات الدموية، نزيف الأنف
· التهاب الأمعاء (التهاب القولون)، التهاب البنكرياس، جفاف الفم، التهاب المعدة، ألم الفم، البواسير
· التهاب الكبد
· تغير لون البشرة في شكل بقع (تشمل البهاق)، جفاف الجلد، احمرار الجلد، سقوط الشعر أو ترقق كثافته على نحو غير معتاد، تغير لون الشعر، الشرى (الطفح الجلدي المصحوب بحكة)، تغير لون الجلد أو اغمقاقه إلى حد غير طبيعي (فرط التصبغ)، جفاف الجلد
· التهاب المفاصل، وهن العضلات، ألم العضلات
· الفشل الكلوي (بما في ذلك التوقف المفاجئ لوظائف الكلى)
· الألم، ألم الصدر، الرعشة
· الشعور بحالة إعياء عامة (التوعك)
غير شائعة (قد تؤثر على 1 من كل 100 شخص)
· وجود الحمض في الدم نتيجة للإصابة بمرض السكري (الحماض الكيتوني السكري)
· ارتفاع مستويات الحمض في الدم
· التهاب الأعصاب المؤقت الذي يسبب الألم والوهن وشلل الأطراف (متلازمة غيلان باريه)، تلف الأعصاب الذي يسبب الخدر والوهن (اعتلال الأعصاب)، تدلي القدم (شلل العصب الشظوي)، التهاب الأعصاب الذي ينتج عن مهاجمة الجسم لنفسه والذي يسبب الخدر أو الوهن أو النخز أو الحرقة (اعتلال الأعصاب المناعي الذاتي)، الوهن العضلي والتعب دون ضمور (الوهن العضلي الوبيل)
· التهاب الدماغ
· التهاب العين (مما قد يُسبب الألم والاحمرار)
· تغيرات في إيقاع أو معدل ضربات القلب، تباطؤ ضربات القلب، التهاب عضلة القلب
· الانثقاب المعوي، التهاب الإثنى عشر، شعور بالحرقة أو الألم في اللسان
· تقشر حاد بالبشرة قد يكون مميتاً (متلازمة ستيفينز جونسون)، مرض جلدي ينتج عن بقع سميكة حمراء ذات حراشف فضية (الصدفية)، مرض جلدي شديد ينتج عن بقع حمراء وحكة، على غرار طفح الحصبة الذي يبدأ في الأطراف وعلى الوجه في بعض الأحيان وبقية أجزاء الجسم (الحمامى متعددة الأشكال)
· طراوة أو وهن العضلات غير الناتجين عن ممارسة التمرينات الرياضية (الاعتلال العضلي)، التهاب العضلات، تيبس العضلات والمفاصل، التهاب في العضلات يتسبب في الألم أو التيبس (ألم العضلات الروماتزمي)، تلف عظام الفك، فتح غير طبيعي بين اثنين من أجزاء الجسم، مثل أحد الأعضاء أو الأوعية الدموية وغيره من الأجزاء (الناسور)
· التهاب الكلى، التهاب المثانة، علامات وأعراض قد تتضمن تبول متكرر أو مؤلم، حاجة ملحة للتبول، دم في البول، ألم ضغط في البطن السفلى
نادرة (قد تؤثر على 1 من كل 1000 شخص)
· التهاب غير معدِ مؤقت وقابل للعلاج في الأغشية الواقية المحيطة بالمخ والحبل الشوكي (التهاب السحايا العقيم)
· الأمراض المزمنة المرتبطة بتراكم الخلايا الالتهابية في مختلف الأعضاء والأنسجة، ولا سيما الرئتين (الساركويد)
· تدهور وظائف الغدة الجار درقية
· مجموعة من المضاعفات الأيضية التي تحدث بعد علاج السرطان الذي يتسم بارتفاع مستويات بوتاسيوم وفوسفات الدم، وانخفاض مستويات كاليسيوم الدم (متلازمة انحلال الورم)
· اضطراب التهابي (مرتبط أصلًا بالمناعة الذاتية) يصيب العينين والجلد وأغشية الأذنين والمخ والحبل الشوكي (متلازمة فوجت كوياناجى هارادا)
· التهاب الأعصاب
· ألم، أو تنميل، أو توخز أو ضعف في الذراعين أو القدمين؛ مشاكل في المثانة أو الأمعاء بما في ذلك الحاجة إلى التبول بشكل أكثر تكراراً، والسلس البولي، وصعوبة التبول والإمساك (التهاب النخاع/التهاب النخاع المستعرض)
· تقشر حاد بالبشرة قد يكون مميتاً (تقشر الأنسجة المتموتة البشروية التسممي)، تغيرات في أي منطقة بالجلد و/أو الأعضاء التناسلية مصحوبة بجفاف وترقق وحكة وألم (الحزاز المتصلب أو غيره من اضطرابات الحزاز)
· مرض مفصلي مزمن (التهاب الفقار المقسط)، مرض يسبب مهاجمة الجهاز المناعي للغدد التي تنتج رطوبة الجسم مثل الدموع واللعاب (متلازمة شوغرن)
آثار جانبية أخرى لا يُعرَف مدى تكرارها (لا يمكن تقدير مدى التكرار من البيانات المتوفرة):
· حالة يقوم بها الجهاز المناعي بإنتاج كمية أكثر من الطبيعي من الخلايا المقاومة للعدوى تسمى المنسجات والخلايا اللمفاوية التي قد تسبب أعراضاً متنوعة (تسمى داء البلعمة)
· رفض زراعة الأعضاء الصلبة
· التهاب غلاف القلب وتراكم السوائل حول القلب (اضطرابات التأمور)
.أخبر طبيبك على الفور إذا لاحظت ظهور أي من الآثار الجانبية السابق ذكرها. ولا تحاول علاج الأعراض التي تظهر عليك بنفسك باستخدام أدوية أخرى.
تغيرات في نتائج الاختبارات
قد يتسبب أوبديفو عند استخدامه وحده أو بالتزامن مع دواء آخر في تغيرات في نتائج الاختبارات التي يجريها الطبيب. وهذا يشمل:
· نتائج غير طبيعية في اختبارات الكبد (زيادة كميات إنزيمات الكبد ناقلة أمين الأسبارتات أو ناقلة أمين الألانين أو ناقلة غاما غلوتاميل أو الفسفاتاز القلوية في الدم، ارتفاع مستويات البيليروبين في الدم)
· نتائج غير طبيعية في اختبارات وظائف الكلى (زيادة كميات الكرياتينين في الدم)
· زيادة مستوى الإنزيم الذي يعمل على تفتيت الدهون والإنزيم الذي يعمل على تفتيت النشا
· ارتفاع أو انخفاض كمية الكالسيوم أو البوتاسيوم
· ارتفاع أو انخفاض مستويات المغنيسيوم أو الصوديوم في الدم
· ارتفاع مستويات الهرمون المنشط للغدة الدرقية.
· ارتفاع مستويات الدهون الثلاثية في الدم
· ارتفاع مستويات الكولسترول في الدم
5. كيفية تخزين أوبديفو
يُحفظ بعيداً عن متناول ومرأى الأطفال.
يُحفظ أوبديفو تحت التبريد في درجة حرارة ما بين 2 إلى 8 مئوية بعيداً عن الضوء عن طريق تخزينه في عبوته الأصلية حتى يحين موعد الاستخدام. لا يُجمد ولا يُرج.
6. معلومات إضافية
ما هي محتويات أوبديفو:
· المادة الفعالة: نيفولوماب
· المكونات غير النشطة: مانيتول، حمض البنتيتيك، بوليسوربات 80، كلوريد الصوديوم، سيترات الصوديوم ثنائي الهيدرات، ماء للحقن. وربما يحتوي هذا الدواء على حمض الهيدروكلوريك وهيدروكسيد الصوديوم أو كليهما.
كيف يبدو أوبديفو وما هي محتويات العبوة:
أوبديفو هو سائل معقم خال من المواد الحافظة ولا يسبب الحمى ما بين صاف إلى براق وشفاف إلى أصفر باهت قد يحتوي على جزيئات خفيفة (قليلة). يأتي دواء أوبديفو (نيفولوماب) للحقن بالتسريب الوريدي في قوارير بكل منها جرعة واحدة.
يتوفر أوبديفو على النحو التالي:
محتويات العلبة الكرتونية:
- قارورة بحجم 40 ملغ/4 مل (10 ملغ/مل) للاستخدام مرة واحدة
- قارورة بحجم 100 ملغ/10 مل (10 ملغ/مل) للاستخدام مرة واحدة
c. مالك حق التسويق والمُصَّنع
مالك حق التسويق
شركة بريستول مايرز سكويب
برنستون، نيوجيرسي 08543 الولايات المتحدة الأمريكية
صنع بواسطة:
بريستول مايرز سكويب هولدينجز فارما، شركة ذات مسؤولية محدودة
بو تييراس نويفاس، الطريق 686، الكيلو ـ2.3
ماناتي، بورتوريكو، 00674، الولايات المتحدة الأمريكية
Unresectable or Metastatic Melanoma
OPDIVO, as a single agent or in combination with ipilimumab, is indicated for the treatment of adult and pediatric patients 12 years and older with unresectable or metastatic melanoma.
Adjuvant Treatment of Melanoma
OPDIVO is indicated for the adjuvant treatment of adult and pediatric patients 12 years and older with completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma.
Neoadjuvant Treatment of Resectable Non-Small Cell Lung Cancer
OPDIVO in combination with platinum-based chemotherapy is indicated for the neoadjuvant treatment of resectable non-small cell lung cancer at high risk of recurrence in adult patients whose tumors have PD-L1 expression ≥ 1% [see Pharmacodynamic properties (5.1) for selection criteria].
Metastatic Non-Small Cell Lung Cancer
· OPDIVO, in combination with ipilimumab and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent NSCLC, with no EGFR or ALK genomic tumor aberrations.
· OPDIVO is indicated for the treatment of adult patients with metastatic NSCLC with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.
Malignant Pleural Mesothelioma
OPDIVO, in combination with ipilimumab, is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma.
Advanced Renal Cell Carcinoma
· OPDIVO, in combination with ipilimumab, is indicated for the first-line treatment of adult patients with intermediate or poor risk advanced RCC.
· OPDIVO, in combination with cabozantinib, is indicated for the first-line treatment of adult patients with advanced RCC.
· OPDIVO as a single agent is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.
Classical Hodgkin Lymphoma
OPDIVO is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after:
· autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin, or
· 3 or more lines of systemic therapy that includes autologous HSCT.
This indication is approved under accelerated approval based on overall response rate [see Pharmacodynamic properties (5.1)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Squamous Cell Carcinoma of the Head and Neck
OPDIVO is indicated for the treatment of adult patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.
Urothelial Carcinoma
OPDIVO is indicated for the adjuvant treatment of adult patients with radical surgical resection, high-risk muscle-invasive urothelial carcinoma who have PD-L expression ≥1.
OPDIVO, in combination with cisplatin and gemcitabine, is indicated for the first-line treatment of adult patients with unresectable or metastatic urothelial carcinoma.
OPDIVO is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who:
· have disease progression during or following platinum-containing chemotherapy.
· have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
Esophageal Cancer
· OPDIVO is indicated for the adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease in adult patients who have received neoadjuvant chemoradiotherapy (CRT).
· OPDIVO in combination with ipilimumab is indicated for the first-line treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma with tumor cell PD-L1 expression ≥ 1%.
· OPDIVO in combination with fluoropyrimidine- and platinum-based combination chemotherapy is indicated for the first-line treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma with tumor cell PD-L1 expression ≥ 1%.
· OPDIVO as monotherapy is indicated for the treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma after prior fluoropyrimidine- and platinum-based combination chemotherapy.
Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma
OPDIVO in combination with fluoropyrimidine- and platinum-based combination chemotherapy is indicated for the first‑line treatment of adult patients with HER2‑negative advanced or metastatic gastric, gastroesophageal junction or esophageal adenocarcinoma whose tumors express PD-L1 with a combined positive score (CPS) ≥ 5.
Treatment must be initiated and supervised by physicians experienced in the treatment of cancer.
PD-L1 testing
If specified in the indication, patient selection for treatment with OPDIVO based on the tumor expression of PD-L1 should be confirmed by a validated test [see Therapeutic indications (4.1), Special warnings and precautions for use (4.4), and Pharmacodynamic properties (5.1)].
Posology
The recommended dosages of OPDIVO as a single agent are presented in Table 1.
Table 1: Recommended Dosages for OPDIVO as a Single Agent | ||
Indication | Recommended OPDIVO Dosage | Duration of Therapy |
Metastatic non-small cell lung cancer | 240 mg every 2 weeks* or 480 mg every 4 weeks*
| Until disease progression or unacceptable toxicity |
Advanced renal cell carcinoma | ||
Classical Hodgkin lymphoma | ||
Squamous cell carcinoma of the head and neck | ||
Locally advanced or metastatic urothelial carcinoma | ||
Esophageal squamous cell carcinoma | ||
Unresectable or metastatic melanoma | Adult patients and pediatric patients age 12 years and older and weighing 40 kg or more: 240 mg every 2 weeks* or 480 mg every 4 weeks* | Until disease progression or unacceptable toxicity |
Pediatric patients age 12 years and older and weighing less than 40 kg: 3 mg/kg every 2 weeks* or 6 mg/kg every 4 weeks* | ||
Adjuvant treatment of melanoma | Adult patients and pediatric patients age 12 years and older and weighing 40 kg or more: 240 mg every 2 weeks* or 480 mg every 4 weeks*
| Until disease recurrence or unacceptable toxicity for up to 1 year |
Pediatric patients age 12 years and older and weighing less than 40 kg: 3 mg/kg every 2 weeks* or 6 mg/kg every 4 weeks* | ||
Adjuvant treatment of urothelial carcinoma (UC) | 240 mg every 2 weeks* or 480 mg every 4 weeks* | Until disease recurrence or unacceptable toxicity for up to 1 year |
Adjuvant treatment of resected esophageal or gastroesophageal junction cancer | 240 mg every 2 weeks* or 480 mg every 4 weeks*
| Until disease progression or unacceptable toxicity for a total treatment duration of 1 year |
* 30-minute intravenous infusion.
The recommended dosages of OPDIVO in combination with other therapeutic agents are presented in Table 2. Refer to the respective Summary of Product Characteristics for each therapeutic agent administered in combination with OPDIVO for the recommended dosage information, as appropriate.
Table 2: Recommended Dosages of OPDIVO in Combination with Other Therapeutic Agents | ||
Indication | Recommended OPDIVO Dosage | Duration of Therapy |
Unresectable or metastatic melanoma | 1 mg/kg every 3 weeks* | In combination with ipilimumab for a maximum of 4 doses or until unacceptable toxicity, whichever occurs earlier |
Adult patients and pediatric patients age 12 years and older and weighing 40 kg or more: 240 mg every 2 weeks* | After completing 4 doses of combination therapy, administer as single agent until disease progression or unacceptable toxicity | |
Pediatric patients age 12 years and older and weighing less than 40 kg: or 6 mg/kg every 4 weeks* | ||
Neoadjuvant treatment of resectable non-small cell lung cancer | 360 mg every 3 weeks* with platinum-based chemotherapy on the same day every 3 weeks | In combination with platinum-based chemotherapy for 3 cycles |
Metastatic or recurrent non-small cell lung cancer | 360 mg every 3 weeks* with ipilimumab 1 mg/kg every 6 weeks* and histology-based platinum doublet chemotherapy every 3 weeks | In combination with ipilimumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression |
2 cycles of histology-based platinum‑doublet chemotherapy | ||
Malignant pleural mesothelioma | 360 mg every 3 weeks* | In combination with ipilimumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression |
Advanced renal cell carcinoma | 3 mg/kg every 3 weeks* | In combination with ipilimumab |
240 mg every 2 weeks* 480 mg every 4 weeks* Administer OPDIVO in combination with cabozantinib 40 mg orally once daily without food | OPDIVO: Until disease progression, unacceptable toxicity, or up to 2 years | |
Cabozantinib: Until disease progression or unacceptable toxicity | ||
240 mg every 2 weeks* | After completing 4 doses of combination therapy with ipilimumab, administer as single agent until disease progression or unacceptable toxicity | |
First-line unresectable or metastatic urothelial carcinoma | 360 mg every 3 weeks* | In combination with cisplatin and gemcitabine |
240 mg every 2 weeks* | After completing up to 6 cycles of combination therapy, administer as single agent until disease progression, unacceptable toxicity, or up to 2 years from first dose | |
Esophageal squamous cell carcinoma | 240 mg every 2 weeks* 480 mg every 4 weeks* Administer OPDIVO in combination with fluoropyrimidine- and platinum‑containing chemotherapy | OPDIVO: Until disease progression, unacceptable toxicity, or up to 2 years |
Chemotherapy: Until disease progression or unacceptable toxicity | ||
3 mg/kg every 2 weeks* | In combination with ipilimumab until disease progression, unacceptable toxicity, or up to 2 years | |
Gastric cancer, Gastroesophageal junction cancer, and Esophageal adenocarcinoma | 240 mg every 2 weeks* or 360 mg every 3 weeks* | Until disease progression, unacceptable toxicity, or up to 2 years |
* 30-minute intravenous infusion on the same day.
Dose Modifications
No dose reduction for OPDIVO is recommended. In general, withhold OPDIVO for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue OPDIVO for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids.
Dosage modifications for OPDIVO or OPDIVO in combination for adverse reactions that require management different from these general guidelines are summarized in Table 3 and Table 4.
When OPDIVO is administered in combination with ipilimumab, withhold or permanently discontinue both ipilimumab and OPDIVO for an adverse reaction meeting these dose modification guidelines.
Table 3: Recommended Dosage Modifications for Adverse Reactions | ||
Adverse Reaction | Severity | Dosage Modification |
Immune-Mediated Adverse Reactions [see Special warnings and precautions for use (4.4)] | ||
Pneumonitis | Grade 2 | Withholda |
Grades 3 or 4 | Permanently discontinue | |
Colitis For colitis in patients treated with combination therapy with ipilimumab, see Table 4. | Grade 2 or 3 | Withholda |
Grade 4 | Permanently discontinue | |
Hepatitis with no tumor involvement of the liver
For liver enzyme elevations in patients treated with combination therapy with ipilimumab, see Table 4. | AST/ALT increases to >3 and ≤8 times ULN or Total bilirubin increases to >1.5 and ≤3 times ULN. | Withholda |
AST or ALT increases to >8 times ULN or Total bilirubin increases to >3 times ULN. | Permanently discontinue | |
Hepatitis with tumor involvement of the liverb
For liver enzyme elevations in patients treated with combination therapy with ipilimumab, see Table 4. | Baseline AST/ALT is >1 and ≤3 times ULN and increases to >5 and ≤10 times ULN or Baseline AST/ALT is >3 and ≤5 times ULN and increases to >8 and ≤10 times ULN. | Withholda |
AST/ALT increases to >10 times ULN or Total bilirubin increases to >3 times ULN. | Permanently discontinue | |
Endocrinopathiesc | Grade 3 or 4 | Withhold until clinically stable or permanently discontinue depending on severity |
Nephritis with Renal Dysfunction | Grade 2 or 3 increased blood creatinine | Withholda |
Grade 4 increased blood creatinine | Permanently discontinue | |
Exfoliative Dermatologic Conditions | Suspected SJS, TEN, or DRESS | Withhold |
Confirmed SJS, TEN, or DRESS | Permanently discontinue | |
Myocarditis | Grades 2, 3, or 4 | Permanently discontinue |
Neurological Toxicities | Grade 2 | Withholda |
Grade 3 or 4 | Permanently discontinue | |
Other Adverse Reactions | ||
Infusion-Related Reactions [see Special warnings and precautions for use (4.4)] | Grade 1 or 2 | Interrupt or slow the rate of infusion |
Grade 3 or 4 | Permanently discontinue | |
a Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day (or equivalent) or less within 12 weeks of initiating steroids.
b If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue OPDIVO based on recommendations for hepatitis with no liver involvement.
c Depending on clinical severity, consider withholding for Grade 2 endocrinopathy until symptom improvement with hormone replacement. Resume once acute symptoms have resolved.
ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit normal.
Table 4: Recommended Dosage Modifications for Adverse Reactions in Patients Treated with Combination Therapy | |||
Treatment | Adverse Reaction | Severity | Dosage Modification |
OPDIVO in combination with ipilimumab | Colitis | Grade 2 | Withholda |
Grade 3 or 4 | Permanently discontinue | ||
Hepatitis with no tumor involvement of the liver or Hepatitis with tumor involvement of the liver/non-HCC | AST/ALT increases to >3 times ULN and ≤5 times ULN or Total bilirubin increases to ≥1.5 and ≤3 times ULN. | Withholda | |
AST or ALT >5 times ULN or Total bilirubin >3 times ULN. | Permanently discontinue | ||
Hepatitis with tumor involvement of the liverb/HCC | Baseline AST/ALT is >1 and ≤3 times ULN and increases to >5 and ≤10 times ULN or Baseline AST/ALT is >3 and ≤5 times ULN and increases to >8 and ≤10 times ULN. | Withholda | |
AST/ALT increases to >10 times ULN or Total bilirubin increases to >3 times ULN. | Permanently discontinue | ||
OPDIVO in combination with cabozantinib | Liver enzyme elevations | ALT or AST >3 times ULN but ≤10 times ULN with concurrent total bilirubin <2 times ULN | Withholdc both OPDIVO and cabozantinib until adverse reactions recoverd to Grades 0-1 |
ALT or AST >10 times ULN or >3 times ULN with concurrent total bilirubin ≥2 times ULN | Permanently discontinuec both OPDIVO and cabozantinib | ||
a Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day (or equivalent) or less within 12 weeks of initiating steroids.
b If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue OPDIVO in combination with ipilimumab based on recommendations for hepatitis with no liver involvement.
c Consider corticosteroid therapy for hepatic adverse reactions if OPDIVO is withheld or discontinued when administered in combination with cabozantinib.
d After recovery, rechallenge with one or both of OPDIVO and cabozantinib may be considered. If rechallenging with cabozantinib with or without OPDIVO, refer to cabozantinib Prescribing Information.
Special Populations
Renal Impairment
Based on the population pharmacokinetic (PK) results, no dose adjustment is required in patients with mild or moderate renal impairment [see Pharmacokinetic properties (5.2)]. Data from patients with severe renal impairment are too limited to draw conclusions on this population.
Hepatic Impairment
Based on the population PK results, no dose adjustment is required in patients with mild hepatic impairment [see Pharmacokinetic properties (5.2)]. Data from patients with moderate or severe hepatic impairment are too limited to draw conclusions on these populations. OPDIVO must be administered with caution in patients with moderate (total bilirubin >1.5 × to 3 × the upper limit of normal [ULN] and any AST) or severe (total bilirubin > 3 × ULN and any AST) hepatic impairment.
Administration
For preparation instructions, see Special precautions for disposal and other handling (6.6).
Administration
· Administer the infusion, after dilution, over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer).
· Administer OPDIVO in combination with other therapeutic agents as follows:
o With ipilimumab: administer OPDIVO first followed by ipilimumab on the same day.
o With platinum-doublet chemotherapy: administer OPDIVO first followed by platinum‑doublet chemotherapy on the same day.
o With ipilimumab and platinum-doublet chemotherapy: administer OPDIVO first followed by ipilimumab and then platinum-doublet chemotherapy on the same day.
o With fluoropyrimidine- and platinum-containing chemotherapy: administer OPDIVO first followed by fluoropyrimidine- and platinum-containing chemotherapy on the same day.
· Use separate infusion bags and filters for each infusion.
· Flush the intravenous line at end of infusion.
· Do not co-administer other drugs through the same intravenous line.
Assessment of PD-L1 status
When assessing the PD-L1 status of the tumor, it is important that a well-validated and robust methodology is used.
Severe and Fatal Immune-Mediated Adverse Reactions
OPDIVO is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under Special warnings and precautions for use may not include all possible severe and fatal immune-mediated reactions.
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.
Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.
Withhold or permanently discontinue OPDIVO depending on severity [see Posology and method of administration (4.2)]. In general, if OPDIVO requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.
Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.
Immune-Mediated Pneumonitis
OPDIVO can cause immune-mediated pneumonitis, which is defined as requiring use of steroids and no clear alternate etiology. In patients treated with other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation.
Immune-Mediated Colitis
OPDIVO can cause immune-mediated colitis, defined as requiring use of corticosteroids and no clear alternate etiology. A common symptom included in the definition of colitis was diarrhea.
Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.
Immune-Mediated Hepatitis and Hepatotoxicity
OPDIVO can cause immune-mediated hepatitis, defined as requiring the use of corticosteroids and no clear alternate etiology.
Immune-Mediated Endocrinopathies
Adrenal Insufficiency
OPDIVO can cause primary or secondary adrenal insufficiency. For grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold OPDIVO depending on severity [see Posology and method of administration (4.2)].
Hypophysitis
OPDIVO can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue OPDIVO depending on severity [see Posology and method of administration (4.2)].
Thyroid Disorders
OPDIVO can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement or medical management as clinically indicated. Withhold or permanently discontinue OPDIVO depending on severity [see Posology and method of administration (4.2)].
Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis
Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold OPDIVO depending on severity [see Posology and method of administration (4.2)].
Immune-Mediated Nephritis with Renal Dysfunction
OPDIVO can cause immune-mediated nephritis, which is defined as requiring use of steroids and no clear alternate etiology.
Immune-Mediated Dermatologic Adverse Reactions
OPDIVO can cause immune-mediated rash or dermatitis, defined as requiring the use of steroids and no clear alternate etiology. Exfoliative dermatitis, including Stevens-Johnson Syndrome, toxic epidermal necrolysis (TEN), and DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue OPDIVO depending on severity [see Posology and method of administration (4.2)].
Other Immune-Mediated Adverse Reactions
[See Undesirable effects (4.8) Description of selected adverse reactions (c)].
Infusion-Related Reactions
OPDIVO can cause severe infusion-related reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue OPDIVO in patients with severe or life-threatening infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion-related reactions [see Posology and method of administration (4.2)].
Complications of Allogeneic Hematopoietic Stem Cell Transplantation
Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1 receptor blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause) [see Undesirable effects (4.8)]. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.
Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1 receptor blocking antibody prior to or after an allogeneic HSCT.
Embryo-Fetal Toxicity
Based on its mechanism of action and data from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for 5 months after the last dose [see Fertility, pregnancy and lactation (4.6)].
Increased Mortality in Patients with Multiple Myeloma when OPDIVO Is Added to a Thalidomide Analogue and Dexamethasone
In randomized clinical trials in patients with multiple myeloma, the addition of a PD-1 blocking antibody, including OPDIVO, to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.
When OPDIVO 3 mg/kg every 3 weeks was administered in combination with ipilimumab 1 mg/kg every 3 weeks, the CL of nivolumab and ipilimumab were unchanged compared to nivolumab or ipilimumab administered alone.
When OPDIVO 1 mg/kg every 3 weeks was administered in combination with ipilimumab 3 mg/kg every 3 weeks, the CL of nivolumab was increased by 29% compared to OPDIVO administered alone and the CL of ipilimumab was unchanged compared to ipilimumab administered alone.
When OPDIVO 3 mg/kg every 2 weeks was administered in combination with ipilimumab 1 mg/kg every 6 weeks, the CL of nivolumab was unchanged compared to OPDIVO administered alone and the CL of ipilimumab was increased by 30% compared to ipilimumab administered alone.
When OPDIVO 360 mg every 3 weeks was administered in combination with ipilimumab 1 mg/kg every 6 weeks and chemotherapy, the CL of nivolumab was unchanged compared to OPDIVO administered alone and the CL of ipilimumab increased by 22% compared to ipilimumab administered alone.
Geriatric Use
Single Agent
Of 3569 patients with melanoma, NSCLC, renal cell carcinoma, urothelial carcinoma, ESCC, and esophageal or gastroesophageal junction cancer who were randomized to single agent OPDIVO in clinical studies, 41% were 65 years and over and 10% were 75 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients [see Pharmacodynamic properties (5.1)].
In patients with cHL or recurrent head and neck SCC who were treated with single agent OPDIVO in clinical studies did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients [see Pharmacodynamic properties (5.1)].
In Combination with Ipilimumab
Of the 314 patients with melanoma who were randomized to OPDIVO in combination with ipilimumab, 41% were 65 years or older and 11% were 75 years or older. No overall differences in safety or effectiveness were reported between elderly patients and younger patients [see Pharmacodynamic properties (5.1)].
Of the 576 patients with NSCLC who were randomized to OPDIVO in combination with ipilimumab, 48% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was a higher discontinuation rate due to adverse reactions in patients aged 75 years or older (29%) relative to all patients who received OPDIVO with ipilimumab (18%). Of the 396 patients in the primary efficacy population (PD-L1 ≥1%) randomized to OPDIVO in combination with ipilimumab, the hazard ratio for overall survival was 0.70 (95% CI: 0.55, 0.89) in the 199 patients younger than 65 years compared to 0.91 (95% CI: 0.72, 1.15) in the 197 patients 65 years or older [see Pharmacodynamic properties (5.1)].
Of the 303 patients with malignant pleural mesothelioma who were randomized to OPDIVO in combination with ipilimumab, 77% were 65 years old or older and 26% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there were higher rates of serious adverse reactions and discontinuation due to adverse reactions in patients aged 75 years or older (68% and 35%, respectively) relative to all patients who received OPDIVO with ipilimumab (54% and 28%, respectively). For patients aged 75 years or older who received chemotherapy, the rate of serious adverse reactions was 34% and the discontinuation rate due to adverse reactions was 26% relative to 28% and 19% respectively for all patients. The hazard ratio for overall survival was 0.76 (95% CI: 0.52, 1.11) in the 71 patients younger than 65 years compared to 0.74 (95% CI: 0.59, 0.93) in the 232 patients 65 years or older randomized to OPDIVO in combination with ipilimumab [see Pharmacodynamic properties (5.1)].
Of the 550 patients with renal cell carcinoma who were randomized to OPDIVO in combination with ipilimumab, 38% were 65 years or older and 8% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients. In elderly patients with intermediate or poor risk, no overall difference in effectiveness was reported [see Pharmacodynamic properties (5.1)].
Of the 325 patients with ESCC who were randomized to OPDIVO in combination with ipilimumab, 43% were 65 years old or older and 7% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was a higher discontinuation rate due to adverse reactions in patients aged 75 years or older (38%) relative to all patients who received OPDIVO with ipilimumab (23%). For patients aged 75 years or older who received chemotherapy, the discontinuation rate due to adverse reactions was 33% relative to 23% for all patients [see Pharmacodynamic properties (5.1)].
In Combination with Platinum-Containing Chemotherapy
Of the 179 patients with NSCLC who were randomized to OPDIVO in combination with platinum-doublet chemotherapy, 48% were 65 years old or older and 6% were 75 years old or older. No overall differences in safety or effectiveness were reported between patients older and younger than 65 years [see Pharmacodynamic properties (5.1)].
Of the 1,110 patients with ESCC, GC, GEJC, or EAC who were randomized to OPDIVO in combination with fluoropyrimidine- and platinum-containing chemotherapy), 42% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients [see Pharmacodynamic properties (5.1)].
Of the 304 patients with UC who were treated with OPDIVO in combination with gemcitabine and platinum-doublet chemotherapy, 40% were 65 years or older and 11% were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years of age and over and younger patients. Clinical studies of OPDIVO with platinum-doublet chemotherapy did not include sufficient numbers of patients aged 75 years and over to determine whether safety and effectiveness differs compared to younger patients [see Pharmacodynamic properties (5.1)].
In Combination with Ipilimumab and Platinum-Doublet Chemotherapy
Of the 361 patients with NSCLC who were randomized to OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy, 51% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was a higher discontinuation rate due to adverse reactions in patients aged 75 years or older (43%) relative to all patients who received OPDIVO with ipilimumab and chemotherapy (24%). For patients aged 75 years or older who received chemotherapy only, the discontinuation rate due to adverse reactions was 16% relative to all patients who had a discontinuation rate of 13%. Based on an updated analysis for overall survival, of the 361 patients randomized to OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy, the hazard ratio for overall survival was 0.61 (95% CI: 0.47, 0.80) in the 176 patients younger than 65 years compared to 0.73 (95% CI: 0.56, 0.95) in the 185 patients 65 years or older [see Pharmacodynamic properties (5.1)].
In Combination with Cabozantinib
Of the 320 patients with renal cell carcinoma who were treated with OPDIVO in combination with cabozantinib, 41% were 65 years or older and 9% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients [see Pharmacodynamic properties (5.1)].
Pediatric population
The safety and effectiveness of OPDIVO have been established in pediatric patients aged 12 years and older for the following indications: as a single agent and in combination with ipilimumab for the treatment of unresectable or metastatic melanoma and as a single agent for the adjuvant treatment of completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma. Use of OPDIVO for these indications is supported by evidence from adequate and well-controlled studies in adults with melanoma and additional pharmacokinetic data in pediatric patients. Nivolumab exposure in pediatric patients 12 years and older is comparable to that of adults and the courses of melanoma are similar in pediatric patients aged 12 years and older to that of adults to allow extrapolation of safety and efficacy [see undeserble effects (4.8), Pharmacodynamic properties (5.1), Pharmacokinetic properties (5.2)].
The safety and effectiveness of OPDIVO have not been established for pediatric patients younger than 12 years old with melanoma.
The safety and effectiveness of OPDIVO have not been established in pediatric patients with non-small cell lung cancer, malignant pleural mesothelioma, advanced renal cell carcinoma, classical Hodgkin lymphoma, squamous cell carcinoma of the head and neck, urothelial carcinoma, hepatocellular carcinoma, esophageal cancer, gastric cancer, gastroesophageal cancer and esophageal adenocarcinoma.
Pregnancy
Pregnancy Category C
Risk Summary
Based on data from animal studies and its mechanism of action [see Pharmacodynamic properties (5.1)], OPDIVO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death [see Data]. Human IgG4 is known to cross the placental barrier and nivolumab is an immunoglobulin G4 (IgG4); therefore, nivolumab has the potential to be transmitted from the mother to the developing fetus. The effects of OPDIVO are likely to be greater during the second and third trimesters of pregnancy. There are no available data on OPDIVO use in pregnant women to evaluate a drug-associated risk. Advise pregnant women of the potential risk to a fetus.
The background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.
Data
Animal Data
A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to increase fetal loss. The effects of nivolumab on prenatal and postnatal development were evaluated in monkeys that received nivolumab twice weekly from the onset of organogenesis through delivery, at exposure levels of between 9 and 42 times higher than those observed at the clinical dose of 3 mg/kg (based on AUC). Nivolumab administration resulted in a non-dose-related increase in spontaneous abortion and increased neonatal death. Based on its mechanism of action, fetal exposure to nivolumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice. In surviving infants (18 of 32 compared to 11 of 16 vehicle-exposed infants) of cynomolgus monkeys treated with nivolumab, there were no apparent malformations and no effects on neurobehavioral, immunological, or clinical pathology parameters throughout the 6-month postnatal period.
Lactation
Risk Summary
There are no data on the presence of nivolumab in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment and for 5 months after the last dose of OPDIVO.
Females and Males of Reproductive Potential
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating OPDIVO.
Contraception
OPDIVO can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for 5 months following the last dose.
There are no data from the use of nivolumab in pregnant women. Studies in animals have shown embryofetal toxicity [see Preclinical safety data (5.3)]. Human IgG4 is known to cross the placental barrier and nivolumab is an IgG4; therefore, nivolumab has the potential to be transmitted from the mother to the developing fetus. Nivolumab is not recommended during pregnancy and in women of childbearing potential not using effective contraception unless the clinical benefit outweighs the potential risk. Effective contraception should be used for at least 5 months following the last dose of nivolumab.
Fertility
See Preclinical safety data (5.3) section.
Nivolumab or nivolumab in combination with ipilimumab may have a minor influence on the ability to drive and use machines. Because of potential adverse reactions such as fatigue [see Undesirable effects (4.8)], patients should be advised to use caution when driving or operating machinery until they are certain that nivolumab does not adversely affect them.
Data presented below is inclusive of events associated with indications that might not be approved in Saudi Arabia.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
4.8.1 Adverse reactions
Summary of the safety profile
The data in the Undesirable Effects section reflect exposure to OPDIVO as a single agent in 1994 patients enrolled in CHECKMATE-037, CHECKMATE-017, CHECKMATE-057, CHECKMATE-066, CHECKMATE-025, CHECKMATE-067, CHECKMATE-205, CHECKMATE-039 or a single‑arm trial in NSCLC (n=117); OPDIVO 1 mg/kg with ipilimumab 3 mg/kg in patients enrolled in CHECKMATE-067 (n=313), CHECKMATE-040 (n=49), or another randomized trial (n=94); OPDIVO 3 mg/kg administered with ipilimumab 1 mg/kg (n=666) in patients enrolled in CHECKMATE-214 or CHECKMATE-142; OPDIVO 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks in patients enrolled in CHECKMATE-227 (n=576) or CHECKMATE-743 (n=300); OPDIVO 360 mg with ipilimumab 1 mg/kg and 2 cycles of platinum-doublet chemotherapy in CHECKMATE-9LA (n=361); and OPDIVO 240 mg with cabozantinib 40 mg in patients enrolled in CHECKMATE-9ER (n=320).
Unresectable or Metastatic Melanoma
Previously Treated Metastatic Melanoma
The safety of OPDIVO was evaluated in CHECKMATE-037, a randomized, open-label trial in 370 patients with unresectable or metastatic melanoma [see Pharmacodynamic properties (5.1)]. Patients had documented disease progression following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, prior ipilimumab-related Grade 4 adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the initiating event, patients with a condition requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications, a positive test for hepatitis B or C, and a history of HIV. Patients received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102): dacarbazine 1000 mg/m2 intravenously every 3 weeks or carboplatin AUC 6 mg/mL/min and paclitaxel 175 mg/m2 intravenously every 3 weeks. The median duration of exposure was 5.3 months (range: 1 day to 13.8+ months) in OPDIVO-treated patients and was 2 months (range: 1 day to 9.6+ months) in chemotherapy-treated patients. In this ongoing trial, 24% of patients received OPDIVO for >6 months and 3% of patients received OPDIVO for >1 year.
The population characteristics in the OPDIVO group and the chemotherapy group were similar: 66% male, median age 59.5 years, 98% White, baseline Eastern Cooperative Oncology Group (ECOG) performance status 0 (59%) or 1 (41%), 74% with M1c stage disease, 73% with cutaneous melanoma, 11% with mucosal melanoma, 73% received two or more prior therapies for advanced or metastatic disease, and 18% had brain metastasis. There were more patients in the OPDIVO group with elevated lactate dehydrogenase (LDH) at baseline (51% vs. 38%).
Serious adverse reactions occurred in 41% of patients receiving OPDIVO. OPDIVO was discontinued for adverse reactions in 9% of patients. Twenty-six percent of patients receiving OPDIVO had a dose interruption for an adverse reaction. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. The most common adverse reaction (reported in ³20% of patients) was rash.
Previously Untreated Metastatic Melanoma
CHECKMATE-066
The safety of OPDIVO was also evaluated in CHECKMATE-066, a randomized, double-blind, active-controlled trial in 411 previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma [see Pharmacodynamic properties (5.1)]. The trial excluded patients with autoimmune disease and patients requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications. Patients received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=206) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=205). The median duration of exposure was 6.5 months (range: 1 day to 16.6 months) in OPDIVO-treated patients. In this trial, 47% of patients received OPDIVO for >6 months and 12% of patients received OPDIVO for >1 year.
The trial population characteristics in the OPDIVO group and dacarbazine group: 59% male, median age 65 years, 99.5% White, 61% with M1c stage disease, 74% with cutaneous melanoma, 11% with mucosal melanoma, 4% with brain metastasis, and 37% with elevated LDH at baseline. There were more patients in the OPDIVO group with ECOG performance status 0 (71% vs. 59%).
Serious adverse reactions occurred in 36% of patients receiving OPDIVO. Adverse reactions led to permanent discontinuation of OPDIVO in 7% of patients and dose interruption in 26% of patients; no single type of adverse reaction accounted for the majority of OPDIVO discontinuations. Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO.
The most frequent Grade 3 and 4 adverse reactions reported in ³2% of patients receiving OPDIVO were increased gamma-glutamyl transferase (3.9%) and diarrhea (3.4%).
The most common adverse reactions (reported in ³20% of patients and at a higher incidence than in the dacarbazine arm) were fatigue, musculoskeletal pain, rash, and pruritus.
CHECKMATE-067
The safety of OPDIVO, administered with ipilimumab or as a single agent, was evaluated in CHECKMATE-067, a randomized (1:1:1), double-blind trial in 937 patients with previously untreated, unresectable or metastatic melanoma [see Pharmacodynamic properties (5.1)]. The trial excluded patients with autoimmune disease, a medical condition requiring systemic treatment with corticosteroids (more than 10 mg daily prednisone equivalent) or other immunosuppressive medication within 14 days of the start of study therapy, a positive test result for hepatitis B or C, or a history of HIV.
Patients were randomized to receive:
· OPDIVO 1 mg/kg over 60 minutes with ipilimumab 3 mg/kg by intravenous infusion every 3 weeks for 4 doses followed by OPDIVO as a single agent at a dose of 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (OPDIVO and ipilimumab arm; n=313), or
· OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (OPDIVO arm; n=313), or
· Ipilimumab 3 mg/kg by intravenous infusion every 3 weeks for up to 4 doses (ipilimumab arm; n=311).
The median duration of exposure to OPDIVO was 2.8 months (range: 1 day to 36.4 months) for the OPDIVO and ipilimumab arm and 6.6 months (range: 1 day to 36.0 months) for the OPDIVO arm. In the OPDIVO and ipilimumab arm, 39% were exposed to OPDIVO for
³6 months and 30% exposed for >1 year. In the OPDIVO arm, 53% were exposed for ³6 months and 40% for >1 year.
The population characteristics were: 65% male, median age 61 years, 97% White, baseline ECOG performance status 0 (73%) or 1 (27%), 93% with American Joint Committee on Cancer (AJCC) Stage IV disease, 58% with M1c stage disease; 36% with elevated LDH at baseline, 4% with a history of brain metastasis, and 22% had received adjuvant therapy.
Serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the OPDIVO and ipilimumab arm relative to the OPDIVO arm.
The most frequent (³10%) serious adverse reactions in the OPDIVO and ipilimumab arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%). The most frequent adverse reactions leading to discontinuation of both drugs in the OPDIVO and ipilimumab arm and of OPDIVO in the OPDIVO arm, respectively, were colitis (10% and 0.6%), diarrhea (8% and 2.2%), increased ALT (4.8% and 1.0%), increased AST (4.5% and 0.6%), and pneumonitis (1.9% and 0.3%).
The most common (³20%) adverse reactions in the OPDIVO and ipilimumab arm were fatigue, diarrhea, rash, nausea, pyrexia, pruritus, musculoskeletal pain, vomiting, decreased appetite, cough, headache, dyspnea, upper respiratory tract infection, arthralgia, and increased transaminases. The most common (³20%) adverse reactions in the OPDIVO arm were fatigue, rash, musculoskeletal pain, diarrhea, nausea, cough, pruritus, upper respiratory tract infection, decreased appetite, headache, constipation, arthralgia, and vomiting.
Adjuvant Treatment of Melanoma
CHECKMATE-76K
The safety of OPDIVO as a single agent was evaluated in CHECKMATE-76K, a randomized (2:1), double-blind trial in 788 patients with completely resected Stage IIB/C melanoma who received OPDIVO 480 mg by intravenous infusion over 30 minutes every 4 weeks (n=524) or placebo by intravenous infusion over 30 minutes every 4 weeks (n=264) for up to 1 year [see Pharmacodynamic properties (5.1)]. The median duration of exposure was 11 months in patients treated with OPDIVO and 11 months in patients treated with placebo.
Serious adverse reactions occurred in 18% of patients treated with OPDIVO. A fatal adverse reaction occurred in 1 (0.2%) patient (heart failure and acute kidney injury). Permanent discontinuation of OPDIVO due to an adverse reaction occurred in 17% of patients. Adverse reactions which resulted in permanent discontinuation of OPDIVO in >1% of patients included diarrhea (1.1%), arthralgia (1.7%), and rash (1.7%).
Dosage interruptions of OPDIVO due to an adverse reaction occurred in 25% of patients. Adverse reactions which required dosage interruption in >1% of patients included COVID-19 infection, infusion related reaction, diarrhea, arthralgia, and increased ALT.
The most common adverse reactions (reported in ≥20% of patients) were fatigue, musculoskeletal pain, rash, diarrhea, and pruritus.
CHECKMATE-238
The safety of OPDIVO as a single agent was evaluated in CHECKMATE-238, a randomized (1:1), double-blind trial in 905 patients with completely resected Stage IIIB/C or Stage IV melanoma received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=452) or ipilimumab 10 mg/kg by intravenous infusion every 3 weeks for 4 doses then every 12 weeks beginning at Week 24 for up to 1 year (n=453) [see Pharmacodynamic properties (5.1)]. The median duration of exposure was 11.5 months in OPDIVO-treated patients and was 2.7 months in ipilimumab-treated patients. In this ongoing trial, 74% of patients received OPDIVO for >6 months.
Serious adverse reactions occurred in 18% of OPDIVO-treated patients. Study therapy was discontinued for adverse reactions in 9% of OPDIVO-treated patients and 42% of ipilimumab-treated patients. Twenty-eight percent of OPDIVO-treated patients had at least one omitted dose for an adverse reaction. Grade 3 or 4 adverse reactions occurred in 25% of OPDIVO-treated patients.
The most frequent Grade 3 and 4 adverse reactions reported in ³2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase. The most common adverse reactions (at least 20%) were fatigue, diarrhea, rash, musculoskeletal pain, pruritus, headache, nausea, upper respiratory infection, and abdominal pain. The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%).
Neoadjuvant Treatment of Resectable Non-Small Cell Lung Cancer
The safety of OPDIVO in combination with platinum-based chemotherapy was evaluated in CHECKMATE-816, a randomized, open-label, multicenter trial in patients with resectable NSCLC [see Pharmacodynamic properties (5.1)]. Patients received either OPDIVO 360 mg administered in combination with platinum-based chemotherapy administered every 3 weeks for 3 cycles; or platinum-based chemotherapy administered every 3 weeks for 3 cycles.
The median age of patients who received OPDIVO in combination with platinum-based chemotherapy or platinum-based chemotherapy was 65 years (range: 34 – 84); 72% male; 47% White, 50% Asian, and 2% Black/African-American.
Serious adverse reactions occurred in 30% of patients who were treated with OPDIVO in combination with platinum-based chemotherapy. Serious adverse reactions in >2% included pneumonia and vomiting. No fatal adverse reactions occurred in patients who received OPDIVO in combination with platinum-based chemotherapy.
Study therapy with OPDIVO in combination with platinum-based chemotherapy was permanently discontinued for adverse reactions in 10% of patients and 30% had at least one treatment withheld for an adverse reaction. The most common adverse reactions (≥1%) resulting in permanent discontinuation of OPDIVO in combination with platinum-based chemotherapy were anaphylactic reaction (1.7%), acute kidney injury (1.1%), rash (1.1%), and fatigue (1.1%).
The most common (>20%) adverse reactions were nausea, constipation, fatigue, decreased appetite, and rash. The most common Grade 3 or 4 laboratory abnormalities (≥2%) were neutropenia, hyperglycemia, leukopenia, lymphopenia, increased amylase, anemia, thrombocytopenia, and hyponatremia.
Metastatic Non-Small Cell Lung Cancer
First-line Treatment of Metastatic or Recurrent NSCLC: In Combination with Ipilimumab and Platinum-Doublet Chemotherapy
The safety of OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy was evaluated in CHECKMATE-9LA [see Pharmacodynamic properties (5.1)]. Patients received either OPDIVO 360 mg administered every 3 weeks in combination with ipilimumab 1 mg/kg administered every 6 weeks and platinum-doublet chemotherapy administered every 3 weeks for 2 cycles; or platinum-doublet chemotherapy administered every 3 weeks for 4 cycles. The median duration of therapy in OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy was 6 months (range: 1 day to 19 months): 50% of patients received OPDIVO and ipilimumab for >6 months and 13% of patients received OPDIVO and ipilimumab for >1 year.
Serious adverse reactions occurred in 57% of patients who were treated with OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy. The most frequent (>2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia.
Study therapy with OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy was permanently discontinued for adverse reactions in 24% of patients and 56% had at least one treatment withheld for an adverse reaction. The most common (>20%) adverse reactions were fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus.
Second-line Treatment of Metastatic NSCLC
The safety of OPDIVO was evaluated in CHECKMATE-017, a randomized open-label, multicenter trial in patients with metastatic squamous NSCLC and progression on or after one prior platinum doublet-based chemotherapy regimen and in CHECKMATE-057, a randomized, open-label, multicenter trial in patients with metastatic non-squamous NSCLC and progression on or after one prior platinum doublet-based chemotherapy regimen [see Pharmacodynamic properties (5.1)]. These trials excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or with symptomatic interstitial lung disease. Patients received OPDIVO 3 mg/kg over 60 minutes by intravenous infusion every 2 weeks or docetaxel 75 mg/m2 intravenously every 3 weeks. The median duration of therapy in OPDIVO-treated patients in CHECKMATE-017 was 3.3 months (range: 1 day to 21.7+ months) and in CHECKMATE-057 was 2.6 months (range: 0 to 24.0+ months). In CHECKMATE-017, 36% of patients received OPDIVO for at least 6 months and 18% of patients received OPDIVO for at least 1 year and in CHECKMATE-057, 30% of patients received OPDIVO for >6 months and 20% of patients received OPDIVO for >1 year.
Across both trials, the median age of OPDIVO-treated patients was 61 years (range: 37 to 85); 38% were ³65 years of age, 61% were male, and 91% were White. Ten percent of patients had brain metastases and ECOG performance status was 0 (26%) or 1 (74%).
In CHECKMATE-057, in the OPDIVO arm, seven deaths were due to infection including one case of Pneumocystis jirovecii pneumonia, four were due to pulmonary embolism, and one death was due to limbic encephalitis. Serious adverse reactions occurred in 46% of patients receiving OPDIVO. OPDIVO was discontinued in 11% of patients and was delayed in 28% of patients for an adverse reaction.
The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. Across both trials, the most common adverse reactions (³20%) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite.
Malignant Pleural Mesothelioma
The safety of OPDIVO in combination with ipilimumab was evaluated in CHECKMATE-743, a randomized, open-label trial in patients with previously untreated unresectable malignant pleural mesothelioma [see Pharmacodynamic properties (5.1)]. Patients received either OPDIVO 3 mg/kg over 30 minutes by intravenous infusion every 2 weeks and ipilimumab 1 mg/kg over 30 minutes by intravenous infusion every 6 weeks for up to 2 years; or platinum-doublet chemotherapy for up to 6 cycles. The median duration of therapy in OPDIVO and ipilimumab‑treated patients was 5.6 months (range: 0 to 26.2 months); 48% of patients received OPDIVO and ipilimumab for >6 months and 24% of patients received OPDIVO and ipilimumab for >1 year.
Serious adverse reactions occurred in 54% of patients who were treated with OPDIVO in combination with ipilimumab. The most frequent (≥2%) serious adverse reactions were pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism. Fatal adverse reactions occurred in 4 (1.3%) patients and included pneumonitis, acute heart failure, sepsis and encephalitis.
Both OPDIVO and ipilimumab were permanently discontinued due to adverse reactions in 23% of patients and 52% had at least one dose withheld due to an adverse reaction.
The most common (≥20%) adverse reactions were fatigue, musculoskeletal pain, rash, diarrhea, dyspnea, nausea, decreased appetite, cough, and pruritus.
Advanced Renal Cell Carcinoma
First-line Renal Cell Carcinoma
CHECKMATE-214
The safety of OPDIVO with ipilimumab was evaluated in CHECKMATE-214, a randomized open-label trial in 1082 patients with previously untreated advanced RCC received OPDIVO 3 mg/kg over 60 minutes with ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses followed by OPDIVO as a single agent at a dose of 3 mg/kg by intravenous infusion every 2 weeks (n=547) or sunitinib 50 mg orally daily for the first 4 weeks of a 6-week cycle (n=535) [see Pharmacodynamic properties (5.1)]. The median duration of treatment was 7.9 months (range: 1 day to 21.4+ months) in OPDIVO and ipilimumab-treated patients and 7.8 months (range: 1 day to 20.2+ months) in sunitinib-treated patients. In this trial, 57% of patients in the OPDIVO and ipilimumab arm were exposed to treatment for >6 months and 38% of patients were exposed to treatment for >1 year.
Serious adverse reactions occurred in 59% of patients receiving OPDIVO and ipilimumab. Study therapy was discontinued for adverse reactions in 31% of OPDIVO and ipilimumab patients. Fifty-four percent (54%) of patients receiving OPDIVO and ipilimumab had a dose interruption for an adverse reaction.
The most frequent serious adverse reactions reported in ³2% of patients treated with OPDIVO and ipilimumab were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis; in patients treated with sunitinib, they were pneumonia, pleural effusion, and dyspnea. The most common adverse reactions (reported in ³20% of patients) were fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite. The most common laboratory abnormalities which have worsened compared to baseline in ³30% of OPDIVO and ipilimumab-treated patients include increased lipase, anemia, increased creatinine, increased ALT, increased AST, hyponatremia, increased amylase, and lymphopenia.
CHECKMATE-9ER
The safety of OPDIVO with cabozantinib was evaluated in CHECKMATE-9ER, a randomized, open-label study in patients with previously untreated advanced RCC. Patients received OPDIVO 240 mg over 30 minutes every 2 weeks with cabozantinib 40 mg orally once daily (n=320) or sunitinib 50 mg daily, administered orally for 4 weeks on treatment followed by 2 weeks off (n=320) [see Pharmacodynamic properties (5.1)]. Cabozantinib could be interrupted or reduced to 20 mg daily or 20 mg every other day. The median duration of treatment was 14 months (range: 0.2 to 27 months) in OPDIVO and cabozantinib-treated patients. In this trial, 82% of patients in the OPDIVO and cabozantinib arm were exposed to treatment for >6 months and 60% of patients were exposed to treatment for >1 year.
Serious adverse reactions occurred in 48% of patients receiving OPDIVO and cabozantinib. The most frequent (³2%) serious adverse reactions were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients.
Adverse reactions leading to discontinuation of either OPDIVO or cabozantinib occurred in 20% of patients: 7% OPDIVO only, 8% cabozantinib only, and 6% both drugs due to same adverse reaction at the same time. Adverse reaction leading to dose interruption or reduction of either OPDIVO or cabozantinib occurred in 83% of patients: 3% OPDIVO only, 46% cabozantinib only, and 21% both drugs due to same adverse reaction at the same time, and 6% both drugs sequentially.
The most common adverse reactions reported in ³20% of patients treated with OPDIVO and cabozantinib were diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia syndrome, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.
Previously Treated Renal Cell Carcinoma
CHECKMATE-025
The safety of OPDIVO was evaluated in CHECKMATE-025, a randomized open-label trial in 803 patients with advanced RCC who had experienced disease progression during or after at least one anti-angiogenic treatment regimen received OPDIVO 3 mg/kg over 60 minutes by intravenous infusion every 2 weeks (n=406) or everolimus 10 mg daily (n=397) [see Pharmacodynamic properties (5.1)]. The median duration of treatment was 5.5 months (range: 1 day to 29.6+ months) in OPDIVO-treated patients and 3.7 months (range: 6 days to 25.7+ months) in everolimus-treated patients.
Rate of death on treatment or within 30 days of the last dose was 4.7% on the OPDIVO arm. Serious adverse reactions occurred in 47% of patients receiving OPDIVO. Study therapy was discontinued for adverse reactions in 16% of OPDIVO patients. Forty-four percent (44%) of patients receiving OPDIVO had a dose interruption for an adverse reaction.
The most frequent serious adverse reactions in at least 2% of patients were: acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. The most common adverse reactions (³20%) were fatigue, cough, nausea, rash, dyspnea, diarrhea, constipation, decreased appetite, back pain, and arthralgia. The most common laboratory abnormalities which have worsened compared to baseline in ³30% of patients include increased creatinine, lymphopenia, anemia, increased AST, increased alkaline phosphatase, hyponatremia, increased triglycerides, and hyperkalemia. In addition, among patients with TSH <ULN at baseline, a greater proportion of patients experienced a treatment-emergent elevation of TSH >ULN in the OPDIVO group compared to the everolimus group (26% and 14%, respectively).
Classical Hodgkin Lymphoma
The safety of OPDIVO was evaluated in 266 adult patients with cHL (243 patients in the CHECKMATE-205 and 23 patients in the CHECKMATE-039 trials) [see Pharmacodynamic properties (5.1)]. Patients received OPDIVO 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks until disease progression, maximal clinical benefit, or unacceptable toxicity.
The median age was 34 years (range: 18 to 72), 98% of patients had received autologous HSCT, none had received allogeneic HSCT, and 74% had received brentuximab vedotin. The median number of prior systemic regimens was 4 (range: 2 to 15). Patients received a median of 23 doses (cycles) of OPDIVO (range: 1 to 48), with a median duration of therapy of 11 months (range: 0 to 23 months).
Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last nivolumab dose, 2 from infection 8 to 9 months after completing nivolumab, and 6 from complications of allogeneic HSCT. Serious adverse reactions occurred in 26% of patients. Dose delay for an adverse reaction occurred in 34% of patients. OPDIVO was discontinued due to adverse reactions in 7% of patients.
The most frequent serious adverse reactions reported in ³1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. The most common adverse reactions (³20%) among all patients were upper respiratory tract infection, fatigue, cough, diarrhea, pyrexia, musculoskeletal pain, rash, nausea, and pruritus.
Squamous Cell Carcinoma of the Head and Neck
The safety of OPDIVO was evaluated in CHECKMATE-141, a randomized, active-controlled, open-label, multicenter trial in patients with recurrent or metastatic SCCHN with progression during or within 6 months of receiving prior platinum-based therapy [see Pharmacodynamic properties (5.1)]. The trial excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary histology, salivary gland or non-squamous histologies (e.g., mucosal melanoma). Patients received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=236) or investigator’s choice of either cetuximab (400 mg/m2 initial dose intravenously followed by 250 mg/m2 weekly), or methotrexate (40 to 60 mg/m2 intravenously weekly), or docetaxel (30 to 40 mg/m2 intravenously weekly). The median duration of exposure to nivolumab was 1.9 months (range: 1 day to 16.1+ months) in OPDIVO-treated patients. In this trial, 18% of patients received OPDIVO for >6 months and 2.5% of patients received OPDIVO for >1 year.
The median age of all randomized patients was 60 years (range: 28 to 83); 28% of patients in the OPDIVO group were ³65 years of age and 37% in the comparator group were ³65 years of age, 83% were male and 83% were White, 12% were Asian, and 4% were Black. Baseline ECOG performance status was 0 (20%) or 1 (78%), 45% of patients received only one prior line of systemic therapy, the remaining 55% of patients had two or more prior lines of therapy, and 90% had prior radiation therapy.
Serious adverse reactions occurred in 49% of patients receiving OPDIVO. OPDIVO was discontinued in 14% of patients and was delayed in 24% of patients for an adverse reaction. Adverse reactions and laboratory abnormalities occurring in patients with SCCHN were generally similar to those occurring in patients with melanoma and NSCLC.
The most frequent serious adverse reactions reported in ³2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. The most common adverse reactions occurring in ³10% of OPDIVO-treated patients and at a higher incidence than investigator’s choice were cough and dyspnea. The most common laboratory abnormalities occurring in ≥10% of OPDIVO-treated patients and at a higher incidence than investigator’s choice were increased alkaline phosphatase, increased amylase, hypercalcemia, hyperkalemia, and increased TSH.
Urothelial Carcinoma
Adjuvant Treatment of Urothelial Carcinoma (UC)
The safety of OPDIVO was evaluated in CHECKMATE-274, a randomized, double‑blind, multicenter trial of adjuvant OPDIVO versus placebo in adult patients who had undergone radical resection of UC originating in the bladder or upper urinary tract (renal pelvis or ureter) and were at high risk of recurrence [see Pharmacodynamic properties (5.1)]. Patients received OPDIVO 240 mg by intravenous infusion over 30 minutes every 2 weeks (n=351) or placebo (n=348) until recurrence or unacceptable toxicity for a maximum of 1 year. The median duration of OPDIVO treatment was 8.8 months (range: 0 to 12.5).
Serious adverse reactions occurred in 30% of OPDIVO patients. The most frequent serious adverse reaction reported in ³2% of patients was urinary tract infection. Fatal adverse reactions occurred in 1% of patients; these included events of pneumonitis (0.6%). OPDIVO was discontinued for adverse reactions in 18% of patients. OPDIVO was delayed for adverse reaction in 33% of patients.
The most common adverse reactions (reported in ³20% of patients) were rash, fatigue, diarrhea, pruritus, musculoskeletal pain, and urinary tract infection.
First-line Treatment of Unresectable or Metastatic UC
The safety of OPDIVO was evaluated in CHECKMATE-901, a randomized, open-label trial in cisplatin-eligible patients with unresectable or metastatic UC [see Pharmacodynamic properties (5.1)]. Patients received either OPDIVO 360 mg with cisplatin and gemcitabine every 3 weeks for up to 6 cycles followed by single-agent OPDIVO 480 mg every 4 weeks up to 2 years (n=304), or cisplatin and gemcitabine chemotherapy every 3 weeks for up to 6 cycles (n=288). Patients discontinuing cisplatin alone were permitted to switch to carboplatin.
Among patients who received OPDIVO with chemotherapy, the median duration of OPDIVO exposure was 7.4 months (range: 0.03 to 47.9 months). Serious adverse reactions occurred in 48% of patients receiving OPDIVO in combination with chemotherapy. The most frequent serious adverse reactions reported in ≥2% of patients who received OPDIVO with chemotherapy were urinary tract infection (4.9%), acute kidney injury (4.3%), anemia (3%), pulmonary embolism (2.6%), sepsis (2.3%), and platelet count decreased (2.3%). The most common adverse reactions (reported in ≥20% of patients) were nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, and peripheral neuropathy.
Fatal adverse reactions occurred in 3.6% of patients who received OPDIVO in combination with chemotherapy; these included sepsis (1%).
OPDIVO and/or chemotherapy were discontinued in 30% of patients and were delayed in 67% of patients for an adverse reaction.
Previously Treated Advanced or Metastatic UC
The safety of OPDIVO was evaluated in CHECKMATE-275, a single-arm trial in which 270 patients with locally advanced or metastatic UC had disease progression during or following platinum-containing chemotherapy or had disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy [see Pharmacodynamic properties (5.1)]. Patients received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. The median duration of treatment was 3.3 months (range: 0 to 13.4+). Forty-six percent (46%) of patients had a dose interruption for an adverse reaction.
Fourteen patients (5.2%) died from causes other than disease progression. This includes 4 patients (1.5%) who died from pneumonitis or cardiovascular failure which was attributed to treatment with OPDIVO. Serious adverse reactions occurred in 54% of patients. OPDIVO was discontinued for adverse reactions in 17% of patients.
The most frequent serious adverse reactions reported in ³2% of patients were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. The most common adverse reactions (reported in ≥20% of patients) were fatigue, musculoskeletal pain, nausea, and decreased appetite.
Esophageal Cancer
Adjuvant Treatment of Resected Esophageal or Gastroesophageal Junction Cancer
The safety of OPDIVO was evaluated in CHECKMATE-577, a randomized, placebo-controlled, double-blinded, multicenter trial in 792 treated patients with completely resected (negative margins) esophageal or gastroesophageal junction cancer who had residual pathologic disease following chemoradiotherapy (CRT) [see Pharmacodynamic properties (5.1)]. The trial excluded patients who did not receive concurrent CRT prior to surgery, had stage IV resectable disease, autoimmune disease, or any condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive medications. Patients received either OPDIVO 240 mg or placebo by intravenous infusion over 30 minutes every 2 weeks for 16 weeks followed by 480 mg or placebo by intravenous infusion over 30 minutes every 4 weeks beginning at week 17. Patients were treated until disease recurrence, unacceptable toxicity, or for up to 1-year total duration. The median duration of exposure was 10.1 months (range: <0.1 to 14 months) in OPDIVO-treated patients and 9 months (range: <0.1 to 15 months) in placebo-treated patients. Among patients who received OPDIVO, 61% were exposed for >6 months and 54% were exposed for >9 months.
Serious adverse reactions occurred in 33% of patients receiving OPDIVO. A serious adverse reaction reported in ³2% of patients who received OPDIVO was pneumonitis. A fatal adverse reaction of myocardial infarction occurred in one patient who received OPDIVO.
OPDIVO was discontinued in 12% of patients and was delayed in 28% of patients for an adverse reaction.
First-line Treatment of Unresectable Advanced or Metastatic ESCC
The safety of OPDIVO in combination with chemotherapy or in combination with ipilimumab was evaluated in CHECKMATE‑648, a randomized, active-controlled, multicenter, open-label trial in patients with previously untreated unresectable advanced, recurrent or metastatic ESCC [see Pharmacodynamic properties (5.1)]. Patients received one of the following treatments:
· OPDIVO 240 mg on days 1 and 15, 5-FU (fluorouracil) 800 mg/m2/day intravenously on days 1 through 5 (for 5 days), and cisplatin 80 mg/m2 intravenously on day 1 (of a 4‑week cycle).
· OPDIVO 3 mg/kg every 2 weeks in combination with ipilimumab 1 mg/kg every 6 weeks.
· 5-FU (fluorouracil) 800 mg/m2/day intravenously on days 1 through 5 (for 5 days), and cisplatin 80 mg/m2 intravenously on day 1 (of a 4-week cycle).
Among patients who received OPDIVO with chemotherapy, the median duration of exposure was 5.7 months (range: 0.1 to 30.6 months). Among patients who received OPDIVO and ipilimumab, the median duration of exposure was 2.8 months (range: 0 to 24 months).
Serious adverse reactions occurred in 62% of patients receiving OPDIVO in combination with chemotherapy and in 69% of patients receiving OPDIVO in combination with ipilimumab. The most frequent serious adverse reactions reported in ³2% of patients who received OPDIVO with chemotherapy were pneumonia (11%), dysphagia (7%), esophageal stenosis (2.9%), acute kidney injury (2.9%), and pyrexia (2.3%). The most frequent serious adverse reactions reported in ³2% of patients who received OPDIVO with ipilimumab were pneumonia (10%), pyrexia (4.3%), pneumonitis (4%), aspiration pneumonia (3.7%), dysphagia (3.7%), hepatic function abnormal (2.8%), decreased appetite (2.8%), adrenal insufficiency (2.5%), and dehydration (2.5%).
Fatal adverse reactions occurred in 5 (1.6%) patients who received OPDIVO in combination with chemotherapy; these included pneumonitis, pneumatosis intestinalis, pneumonia, and acute kidney injury and in 5 (1.6%) patients who received OPDIVO in combination with ipilimumab; these included pneumonitis, interstitial lung disease, pulmonary embolism, and acute respiratory distress syndrome.
OPDIVO and/or chemotherapy were discontinued in 39% of patients and were delayed in 71% of patients for an adverse reaction. OPDIVO and/or ipilimumab were discontinued in 23% of patients and were delayed in 46% of patients for an adverse reaction.
The most common adverse reactions reported in ≥20% of patients treated with OPDIVO in combination with chemotherapy were nausea, decreased appetite, fatigue, constipation, stomatitis, diarrhea, and vomiting. The most common adverse reactions reported in ≥20% of patients treated with OPDIVO in combination with ipilimumab were rash, fatigue, pyrexia, nausea, diarrhea, and constipation.
Previously-Treated Unresectable Advanced, Recurrent or Metastatic Esophageal Squamous Cell Carcinoma (ESCC)
The safety of OPDIVO was evaluated in ATTRACTION-3, a randomized, active-controlled, open‑label, multicenter trial in 209 patients with unresectable advanced, recurrent or metastatic ESCC refractory or intolerant to at least one fluoropyrimidine- and platinum‑based chemotherapy [see Pharmacodynamic properties (5.1)]. The trial excluded patients who were refractory or intolerant to taxane therapy, had brain metastases that were symptomatic or required treatment, had autoimmune disease, used systemic corticosteroids or immunosuppressants, had apparent tumor invasion of organs adjacent to the esophageal tumor or had stents in the esophagus or respiratory tract. Patients received OPDIVO 240 mg by intravenous infusion over 30 minutes every 2 weeks (n=209) or investigator’s choice: docetaxel 75 mg/m2 intravenously every 3 weeks (n=65) or paclitaxel 100 mg/m2 intravenously once a week for 6 weeks followed by 1 week off (n=143). Patients were treated until disease progression or unacceptable toxicity. The median duration of exposure was 2.6 months (range: 0 to 29.2 months) in OPDIVO-treated patients and 2.6 months (range: 0 to 21.4 months) in docetaxel- or paclitaxel-treated patients. Among patients who received OPDIVO, 26% were exposed for >6 months and 10% were exposed for >1 year.
Serious adverse reactions occurred in 38% of patients receiving OPDIVO. Serious adverse reactions reported in ³2% of patients who received OPDIVO were pneumonia, esophageal fistula, interstitial lung disease and pyrexia. The following fatal adverse reactions occurred in patients who received OPDIVO: interstitial lung disease or pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%), gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%).
OPDIVO was discontinued in 13% of patients and was delayed in 27% of patients for an adverse reaction.
Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma
The safety of OPDIVO in combination with chemotherapy was evaluated in CHECKMATE-649, a randomized, multicenter, open-label trial in patients with previously untreated advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma [see Pharmacodynamic properties (5.1)]. The trial excluded patients who were known human epidermal growth factor receptor 2 (HER2) positive or had untreated central nervous system (CNS) metastases. Patients were randomized to receive OPDIVO in combination with chemotherapy or chemotherapy. Patients received one of the following treatments:
- OPDIVO 240 mg in combination with mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) every 2 weeks or mFOLFOX6 every 2 weeks.
- OPDIVO 360 mg in combination with CapeOX (capecitabine and oxaliplatin) every 3 weeks or CapeOX every 3 weeks.
Patients were treated with OPDIVO in combination with chemotherapy or chemotherapy until disease progression, unacceptable toxicity, or up to 2 years. The median duration of exposure was 6.8 months (range: 0 to 33.5 months) in OPDIVO and chemotherapy-treated patients. Among patients who received OPDIVO and chemotherapy, 54% were exposed for >6 months and 28% were exposed for >1 year.
Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with OPDIVO in combination with chemotherapy; these included pneumonitis (4 patients), febrile neutropenia (2 patients), stroke (2 patients), gastrointestinal toxicity, intestinal mucositis, septic shock, pneumonia, infection, gastrointestinal bleeding, mesenteric vessel thrombosis, and disseminated intravascular coagulation. Serious adverse reactions occurred in 52% of patients treated with OPDIVO in combination with chemotherapy. OPDIVO and/or chemotherapy were discontinued in 44% of patients and at least one dose was withheld in 76% of patients due to an adverse reaction.
The most frequent serious adverse reactions reported in ³2% of patients treated with OPDIVO in combination with chemotherapy were vomiting (3.7%), pneumonia (3.6%), anemia (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). The most common adverse reactions reported in ³20% of patients treated with OPDIVO in combination with chemotherapy were peripheral neuropathy, nausea, fatigue, diarrhea, vomiting, decreased appetite, abdominal pain, constipation, and musculoskeletal pain.
Tabulated summary of adverse reactions
Unresectable or Metastatic Melanoma
Previously Treated Metastatic Melanoma
Tables 5 and 6 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-037.
Table 5: Adverse Reactions Occurring in ³10% of OPDIVO-Treated Patients and at a Higher Incidence than in the Chemotherapy Arm (Between Arm Difference of ³5% All Grades or ³2% Grades 3-4) - CHECKMATE-037 | |||||
| OPDIVO | Chemotherapy | |||
Adverse Reaction | All | Grades | All | Grades | |
Skin and Subcutaneous Tissue |
|
|
|
| |
Rasha | 21 | 0.4 | 7 | 0 | |
Pruritus | 19 | 0 | 3.9 | 0 | |
Respiratory, Thoracic and Mediastinal |
|
|
|
| |
Cough | 17 | 0 | 6 | 0 | |
Infections |
|
|
|
| |
Upper respiratory tract infectionb | 11 | 0 | 2 | 0 | |
General |
|
|
|
| |
Peripheral edema | 10 | 0 | 5 | 0 | |
Peripheral edema | 10 | 0 | 5 | 0 |
Toxicity was graded per NCI CTCAE v4.
a Includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular rash, vesicular rash, and acneiform dermatitis.
b Includes rhinitis, pharyngitis, and nasopharyngitis.
Clinically important adverse reactions in <10% of patients who received OPDIVO were:
Cardiac Disorders: ventricular arrhythmia
Eye Disorders: iridocyclitis
General Disorders and Administration Site Conditions: infusion-related reactions
Investigations: increased amylase, increased lipase
Nervous System Disorders: dizziness, peripheral and sensory neuropathy
Skin and Subcutaneous Tissue Disorders: exfoliative dermatitis, erythema multiforme, vitiligo, psoriasis
Table 6: Laboratory Abnormalities Worsening from Baselinea Occurring in ³10% of OPDIVO-Treated Patients and at a Higher Incidence than in the Chemotherapy Arm (Between Arm Difference of ³5% All Grades or ³2% Grades 3-4) - CHECKMATE-037 | ||||
Laboratory Abnormality | OPDIVO | Chemotherapy | ||
All Grades (%) | Grades 3-4 (%) | All Grades (%) | Grades 3-4 (%) | |
Increased AST | 28 | 2.4 | 12 | 1 |
Hyponatremia | 25 | 5 | 18 | 1.1 |
Increased alkaline phosphatase | 22 | 2.4 | 13 | 1.1 |
Increased ALT | 16 | 1.6 | 5 | 0 |
Hyperkalemia | 15 | 2 | 6 | 0 |
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 252 to 256 patients) and chemotherapy group (range: 94 to 96 patients).
Previously Untreated Metastatic Melanoma
CHECKMATE-066
Tables 7 and 8 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-066.
Table 7: Adverse Reactions Occurring in ³10% of OPDIVO-Treated Patients and at a Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of ³5% All Grades or ³2% Grades 3-4) - CHECKMATE-066 | ||||
| OPDIVO | Dacarbazine | ||
Adverse Reaction | All Grades (%) | Grades 3-4 (%) | All Grades (%) | Grades 3-4 (%) |
General |
|
|
|
|
Fatigue | 49 | 1.9 | 39 | 3.4 |
Edemaa | 12 | 1.5 | 4.9 | 0 |
Musculoskeletal and Connective Tissue |
|
|
|
|
Musculoskeletal painb | 32 | 2.9 | 25 | 2.4 |
Skin and Subcutaneous Tissue |
|
|
|
|
Rashc | 28 | 1.5 | 12 | 0 |
Pruritus | 23 | 0.5 | 12 | 0 |
Vitiligo | 11 | 0 | 0.5 | 0 |
Erythema | 10 | 0 | 2.9 | 0 |
Infections |
|
|
|
|
Upper respiratory tract infectiond | 17 | 0 | 6 | 0 |
Toxicity was graded per NCI CTCAE v4.
a Includes periorbital edema, face edema, generalized edema, gravitational edema, localized edema, peripheral edema, pulmonary edema, and lymphedema.
b Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, pain in jaw, and spinal pain.
c Includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular rash, vesicular rash, dermatitis, allergic dermatitis, exfoliative dermatitis, acneiform dermatitis, drug eruption, and skin reaction.
d Includes rhinitis, viral rhinitis, pharyngitis, and nasopharyngitis.
Clinically important adverse reactions in <10% of patients who received OPDIVO were:
Nervous System Disorders: peripheral neuropathy
Table 8: Laboratory Abnormalities Worsening from Baselinea Occurring in ³10% of OPDIVO-Treated Patients and at a Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of ³5% All Grades or ³2% Grades 3-4) - CHECKMATE-066 | ||||
Laboratory Abnormality
| OPDIVO | Dacarbazine | ||
All Grades (%) | Grades 3-4 (%) | All Grades (%) | Grades 3-4 (%) | |
Increased ALT | 25 | 3 | 19 | 0.5 |
Increased AST | 24 | 3.6 | 19 | 0.5 |
Increased alkaline phosphatase | 21 | 2.6 | 14 | 1.6 |
Increased bilirubin | 13 | 3.1 | 6 | 0 |
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 194 to 197 patients) and dacarbazine group (range: 186 to 193 patients).
CHECKMATE-067
Tables 9 and 10 summarize the incidence of adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-067.
Table 9: Adverse Reactions Occurring in ³10% of Patients on the OPDIVO and Ipilimumab Arm or the OPDIVO Arm and at a Higher Incidence than in the Ipilimumab Arm (Between Arm Difference of ³5% All Grades or ³2% Grades 3‑4) - CHECKMATE-067 | ||||||
Adverse Reaction | OPDIVO and |
(n=313) |
(n=311) | |||
All Grades (%) | Grades | All Grades (%) | Grades | All Grades (%) | Grades | |
General | ||||||
Fatiguea | 62 | 7 | 59 | 1.6 | 51 | 4.2 |
Pyrexia | 40 | 1.6 | 16 | 0 | 18 | 0.6 |
Gastrointestinal | ||||||
Diarrhea | 54 | 11 | 36 | 5 | 47 | 7 |
Nausea | 44 | 3.8 | 30 | 0.6 | 31 | 1.9 |
Vomiting | 31 | 3.8 | 20 | 1 | 17 | 1.6 |
Skin and Subcutaneous Tissue | ||||||
Rashb | 53 | 6 | 40 | 1.9 | 42 | 3.5 |
Vitiligo | 9 | 0 | 10 | 0.3 | 5 | 0 |
Musculoskeletal and Connective Tissue | ||||||
Musculoskeletal painc | 32 | 2.6 | 42 | 3.8 | 36 | 1.9 |
Arthralgia | 21 | 0.3 | 21 | 1 | 16 | 0.3 |
Metabolism and Nutrition | ||||||
Decreased appetite | 29 | 1.9 | 22 | 0 | 24 | 1.3 |
Respiratory, Thoracic and Mediastinal | ||||||
Cough/productive cough | 27 | 0.3 | 28 | 0.6 | 22 | 0 |
Dyspnea/exertional dyspnea | 24 | 2.9 | 18 | 1.3 | 17 | 0.6 |
Infections | ||||||
Upper respiratory tract infectiond | 23 | 0 | 22 | 0.3 | 17 | 0 |
Endocrine | ||||||
Hypothyroidism | 19 | 0.6 | 11 | 0 | 5 | 0 |
Hyperthyroidism | 11 | 1.3 | 6 | 0 | 1 | 0 |
Investigations | ||||||
Decreased weight | 12 | 0 | 7 | 0 | 7 | 0.3 |
Vascular | ||||||
Hypertensione | 7 | 2.2 | 11 | 5 | 9 | 2.3 |
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia and fatigue.
b Includes pustular rash, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, exfoliative dermatitis, psoriasiform dermatitis, drug eruption, exfoliative rash, erythematous rash, generalized rash, macular rash, maculopapular rash, morbilliform rash, papular rash, papulosquamous rash, and pruritic rash.
c Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain.
d Includes upper respiratory tract infection, nasopharyngitis, pharyngitis, and rhinitis.
e Includes hypertension and blood pressure increased.
Clinically important adverse reactions in <10% of patients who received OPDIVO with ipilimumab or OPDIVO as a single agent were:
Gastrointestinal Disorders: stomatitis, intestinal perforation
Skin and Subcutaneous Tissue Disorders: vitiligo
Musculoskeletal and Connective Tissue Disorders: myopathy, Sjogren’s syndrome, spondyloarthropathy, myositis (including polymyositis)
Nervous System Disorders: neuritis, peroneal nerve palsy
Table 10: Laboratory Abnormalities Worsening from Baselinea Occurring in ³20% of Patients Treated with OPDIVO with Ipilimumab or Single-Agent OPDIVO and at a Higher Incidence than in the Ipilimumab Arm (Between Arm Difference of ³5% All Grades or ³2% Grades 3-4) - CHECKMATE-067 | ||||||
Laboratory Abnormality | OPDIVO and |
|
| |||
All Grades (%) | Grade | All Grades (%) | Grade | All Grades (%) | Grade | |
Chemistry | ||||||
Increased ALT | 55 | 16 | 25 | 3 | 29 | 2.7 |
Hyperglycemia | 53 | 5.3 | 46 | 7 | 26 | 0 |
Increased AST | 52 | 13 | 29 | 3.7 | 29 | 1.7 |
Hyponatremia | 45 | 10 | 22 | 3.3 | 26 | 7 |
Increased lipase | 43 | 22 | 32 | 12 | 24 | 7 |
Increased alkaline phosphatase | 41 | 6 | 27 | 2 | 23 | 2 |
Hypocalcemia | 31 | 1.1 | 15 | 0.7 | 20 | 0.7 |
Increased amylase | 27 | 10 | 19 | 2.7 | 15 | 1.6 |
Increased creatinine | 26 | 2.7 | 19 | 0.7 | 17 | 1.3 |
Hematology | ||||||
Anemia | 52 | 2.7 | 41 | 2.6 | 41 | 6 |
Lymphopenia | 39 | 5 | 41 | 4.9 | 29 | 4 |
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and ipilimumab (range: 75 to 297); OPDIVO (range: 81 to 306); ipilimumab (range: 61 to 301).
Adjuvant Treatment of Melanoma
CHECKMATE-76K
Tables 11 and 12 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-76K.
Table 11: Adverse Reactions Occurring in ≥10% of Patients Treated with OPDIVO - CHECKMATE‑76K
Adverse Reaction | OPDIVO | Placebo | |||
All Grades (%) | Grades 3-4 (%) | All Grades (%) | Grades 3-4 (%) | ||
General |
| ||||
Fatiguea | 36 | 0.4 | 34 | 0.4 |
|
Musculoskeletal and connective tissue | |||||
Musculoskeletal painb | 30 | 0.4 | 26 | 0.4 | |
Skin and Subcutaneous Tissue |
| ||||
Rashc | 28 | 1.1 | 15 | 0.4 |
|
Pruritus | 20 | 0.2 | 11 | 0 |
|
Gastrointestinal |
| ||||
Diarrhead | 23 | 1.3 | 16 | 0 |
|
Nausea | 14 | 0 | 11 | 0 |
|
Endocrine |
| ||||
Hypothyroidisme | 14 | 0 | 2.3 | 0 |
|
Nervous system | |||||
Headachef | 12 | 0.2 | 14 | 0.8 | |
Toxicity was graded per NCI CTCAE v5.
a Includes asthenia.
b Includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, spinal pain, pain in extremity.
c Includes dermatitis, dermatitis acneiform, dyshidrotic eczema, eczema, eczema asteatotic, eyelid rash, genital rash, pemphigoid, penile rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, skin exfoliation, toxic skin eruption.
d Includes autoimmune colitis, colitis, diarrhea, enteritis, enterocolitis.
e Includes autoimmune hypothyroidism, blood thyroid stimulating hormone increased.
f Includes cluster headache, migraine.
Table 12: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of OPDIVO-Treated Patients - CHECKMATE-76K | |||||
Laboratory Abnormality | OPDIVO (n=524) | Placebo (n=264) | |||
All Grades (%) | Grades 3-4 (%) | All Grades (%) | Grades 3-4 (%) | ||
Hematology |
|
|
|
| |
Anemia | 19 | 0 | 14 | 0 | |
Lymphopenia | 17 | 1.1 | 17 | 1.7 | |
Neutropenia | 10 | 0 | 10 | 0.4 | |
Chemistry |
|
|
|
| |
AST increased | 25 | 2.2 | 16 | 0.4 | |
Lipase increased | 22 | 2.9 | 21 | 2.3 | |
ALT increased | 20 | 2.1 | 15 | 0.4 | |
Amylase increased | 17 | 0.4 | 9 | 0 | |
Creatinine increased | 15 | 0.4 | 13 | 0 | |
Sodium decreased | 13 | 0.6 | 11 | 0.4 | |
Potassium increased | 13 | 1 | 15 | 1.1 | |
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 262 to 513 patients) and placebo group (range: 138 to 261 patients).
CHECKMATE-238
Tables 13 and 14 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-238.
Table 13: Adverse Reactions Occurring in ³10% of OPDIVO-Treated Patients - CHECKMATE-238 | ||||
Adverse Reaction | OPDIVO | Ipilimumab 10 mg/kg | ||
All Grades (%) | Grades 3-4 (%) | All Grades (%) | Grades 3-4 (%) | |
General | ||||
Fatiguea | 57 | 0.9 | 55 | 2.4 |
Gastrointestinal | ||||
Diarrhea | 37 | 2.4 | 55 | 11 |
Nausea | 23 | 0.2 | 28 | 0 |
Abdominal painb | 21 | 0.2 | 23 | 0.9 |
Constipation | 10 | 0 | 9 | 0 |
Skin and Subcutaneous Tissue | ||||
Rashc | 35 | 1.1 | 47 | 5.3 |
Pruritus | 28 | 0 | 37 | 1.1 |
Musculoskeletal and Connective Tissue | ||||
Musculoskeletal paind | 32 | 0.4 | 27 | 0.4 |
Arthralgia | 19 | 0.4 | 13 | 0.4 |
Nervous System | ||||
Headache | 23 | 0.4 | 31 | 2.0 |
Dizzinesse | 11 | 0 | 8 | 0 |
Infections | ||||
Upper respiratory tract infectionf | 22 | 0 | 15 | 0.2 |
Respiratory, Thoracic and Mediastinal | ||||
Cough/productive cough | 19 | 0 | 19 | 0 |
Dyspnea/exertional dyspnea | 10 | 0.4 | 10 | 0.2 |
Endocrine | ||||
Hypothyroidismg | 12 | 0.2 | 7.5 | 0.4 |
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia.
b Includes abdominal discomfort, lower abdominal pain, upper abdominal pain, and abdominal tenderness.
c Includes dermatitis described as acneiform, allergic, bullous, or exfoliative and rash described as generalized, erythematous, macular, papular, maculopapular, pruritic, pustular, vesicular, or butterfly, and drug eruption.
d Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, spinal pain, and pain in extremity.
e Includes postural dizziness and vertigo.
f Includes upper respiratory tract infection including viral respiratory tract infection, lower respiratory tract infection, rhinitis, pharyngitis, and nasopharyngitis.
g Includes secondary hypothyroidism and autoimmune hypothyroidism.
Table 14: Laboratory Abnormalities Worsening from Baselinea Occurring in ³10% of OPDIVO-Treated Patients - CHECKMATE-238 | ||||
Laboratory Abnormality | OPDIVO | Ipilimumab 10 mg/kg | ||
All Grades (%) | Grades 3-4 (%) | All Grades (%) | Grades 3-4 (%) | |
Hematology |
|
|
|
|
Lymphopenia | 27 | 0.4 | 12 | 0.9 |
Anemia | 26 | 0 | 34 | 0.5 |
Leukopenia | 14 | 0 | 2.7 | 0.2 |
Neutropenia | 13 | 0 | 6 | 0.5 |
Chemistry |
|
|
|
|
Increased Lipase | 25 | 7 | 23 | 9 |
Increased ALT | 25 | 1.8 | 40 | 12 |
Increased AST | 24 | 1.3 | 33 | 9 |
Increased Amylase | 17 | 3.3 | 13 | 3.1 |
Hyponatremia | 16 | 1.1 | 22 | 3.2 |
Hyperkalemia | 12 | 0.2 | 9 | 0.5 |
Increased Creatinine | 12 | 0 | 13 | 0 |
Hypocalcemia | 10 | 0.7 | 16 | 0.5 |
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 400 to 447 patients) and ipilimumab 10 mg/kg group (range: 392 to 443 patients).
Neoadjuvant Treatment of Resectable Non-Small Cell Lung Cancer
Tables 15 and 16 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-816.
Table 15: Adverse Reactions in >10% of Patients with Early-Stage NSCLC Receiving Neoadjuvant OPDIVO and Platinum-Based Chemotherapy in CHECKMATE-816 | ||||
Adverse Reaction | OPDIVO and Platinum-Based Chemotherapy | Platinum-Based Chemotherapy | ||
All Grades (%) | Grades 3 or 4 (%) | All Grades (%) | Grades 3 or 4 (%) | |
Gastrointestinal | ||||
Nausea | 38 | 0.6 | 45 | 1.1 |
Constipation | 34 | 0 | 32 | 1.1 |
Vomiting | 11 | 1.1 | 13 | 0.6 |
General | ||||
Fatiguea | 26 | 2.3 | 23 | 1.1 |
Malaise | 15 | 0.6 | 14 | 0.6 |
Metabolism and Nutrition | ||||
Decreased appetite | 20 | 1.1 | 23 | 2.3 |
Skin and Subcutaneous Tissue | ||||
Rashb | 20 | 2.3 | 7 | 0 |
Alopecia | 11 | 0 | 15 | 0 |
Nervous System | ||||
Peripheral neuropathyc | 13 | 0 | 6 | 0 |
Toxicity was graded per NCI CTCAE v4.
a Includes fatigue and asthenia
b Includes rash, dermatitis, acneiform dermatitis, atopic dermatitis, bullous dermatitis, drug eruption, maculopapular rash, and pruritic rash.
c Includes peripheral neuropathy, dysesthesia, hypoesthesia, peripheral motor neuropathy, peripheral sensory neuropathy.
Table 16: Select Laboratory Values Worsening from Baselinea Occurring in >20% of Patients with Early-Stage NSCLC Receiving Neoadjuvant OPDIVO and Platinum-Based Chemotherapy in CHECKMATE-816 | ||||
Laboratory Abnormality | OPDIVO and Platinum-Based Chemotherapya | Platinum-Based Chemotherapya | ||
All Grades (%) | Grades 3 or 4 (%) | All Grades (%) | Grades 3 or 4 (%) | |
Hematology | ||||
Anemia | 63 | 3.5 | 70 | 6 |
Neutropenia | 58 | 22 | 58 | 27 |
Leukopenia | 53 | 5 | 51 | 11 |
Lymphopenia | 38 | 4.7 | 31 | 1.8 |
Thrombocytopenia | 24 | 2.9 | 22 | 3 |
Chemistry | ||||
Hyperglycemia | 37 | 6 | 35 | 2.9 |
Hypomagnesemia | 25 | 1.2 | 29 | 1.2 |
Hyponatremia | 25 | 2.4 | 28 | 1.8 |
Increased amylase | 23 | 3.6 | 13 | 1.8 |
Increased ALT | 23 | 0 | 20 | 1.2 |
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and platinum-based chemotherapy group (range: 73 to 171 patients) and platinum-based chemotherapy group (range: 68 to 171 patients).
Metastatic Non-Small Cell Lung Cancer
First-line Treatment of Metastatic or Recurrent NSCLC: In Combination with Ipilimumab and Platinum-Doublet Chemotherapy
Tables 17 and 18 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9LA.
Table 17: Adverse Reactions in >10% of Patients Receiving OPDIVO and Ipilimumab and Platinum-Doublet Chemotherapy - CHECKMATE-9LA | ||||
Adverse Reaction | OPDIVO and Ipilimumab and Platinum-Doublet Chemotherapy | Platinum-Doublet Chemotherapy | ||
All Grades (%) | Grades 3-4 (%) | All Grades (%) | Grades 3-4 (%) | |
General | ||||
Fatiguea | 49 | 5 | 40 | 4.9 |
Pyrexia | 14 | 0.6 | 10 | 0.6 |
Musculoskeletal and Connective Tissue | ||||
Musculoskeletal painb | 39 | 4.5 | 27 | 2 |
Gastrointestinal | ||||
Nausea | 32 | 1.7 | 41 | 0.9 |
Diarrheac | 31 | 6 | 18 | 1.7 |
Constipation | 21 | 0.6 | 23 | 0.6 |
Vomiting | 18 | 2 | 17 | 1.4 |
Abdominal paind | 12 | 0.6 | 11 | 0.9 |
Skin and Subcutaneous Tissue | ||||
Rashe | 30 | 4.7 | 10 | 0.3 |
Pruritusf | 21 | 0.8 | 2.9 | 0 |
Alopecia | 11 | 0.8 | 10 | 0.6 |
Metabolism and Nutrition | ||||
Decreased appetite | 28 | 2 | 22 | 1.7 |
Respiratory, Thoracic and Mediastinal | ||||
Coughg | 19 | 0.6 | 15 | 0.9 |
Dyspneah | 18 | 4.7 | 14 | 3.2 |
Endocrine | ||||
Hypothyroidismi | 19 | 0.3 | 3.4 | 0 |
Nervous System | ||||
Headache | 11 | 0.6 | 7 | 0 |
Dizzinessj | 11 | 0.6 | 6 | 0 |
Toxicity was graded per NCI CTCAE v4.
a Includes fatigue and asthenia.
b Includes myalgia, back pain, pain in extremity, musculoskeletal pain, bone pain, flank pain, muscle spasms, musculoskeletal chest pain, musculoskeletal disorder, osteitis, musculoskeletal stiffness, non-cardiac chest pain, arthralgia, arthritis, arthropathy, joint effusion, psoriatic arthropathy, synovitis.
c Includes colitis, ulcerative colitis, diarrhea, and enterocolitis.
d Includes abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, and gastrointestinal pain.
e Includes acne, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, generalized exfoliative dermatitis, eczema, keratoderma blennorrhagica, palmar-plantar erythrodysesthesia syndrome, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, morbilliform rash, papular rash, pruritic rash, skin exfoliation, skin reaction, skin toxicity, Stevens-Johnson syndrome, urticaria.
f Includes pruritus and generalized pruritus.
g Includes cough, productive cough, and upper-airway cough syndrome.
h Includes dyspnea, dyspnea at rest, and exertional dyspnea.
i Includes autoimmune thyroiditis, increased blood thyroid stimulating hormone, hypothyroidism, thyroiditis, and decreased free tri-iodothyronine.
j Includes dizziness, vertigo and positional vertigo.
Clinically important adverse reactions in <10% of patients who received OPDIVO and ipilimumab and platinum-doublet chemotherapy were:
Cardiac disorders: bradycardia
Table 18: Laboratory Values Worsening from Baselinea Occurring in >20% of Patients on OPDIVO and Ipilimumab and Platinum-Doublet Chemotherapy - CHECKMATE-9LA | ||||
Laboratory Abnormality | OPDIVO and Ipilimumab and Platinum-Doublet Chemotherapy | Platinum-Doublet Chemotherapy | ||
Grades 1-4 (%) | Grades 3-4 (%) | Grades 1-4 (%) | Grades 3-4 (%) | |
Hematology | ||||
Anemia | 70 | 9 | 74 | 16 |
Lymphopenia | 41 | 6 | 40 | 11 |
Neutropenia | 40 | 15 | 42 | 15 |
Leukopenia | 36 | 10 | 40 | 9 |
Thrombocytopenia | 23 | 4.3 | 24 | 5 |
Chemistry | ||||
Hyperglycemia | 45 | 7 | 42 | 2.6 |
Hyponatremia | 37 | 10 | 27 | 7 |
Increased ALT | 34 | 4.3 | 24 | 1.2 |
Increased lipase | 31 | 12 | 10 | 2.2 |
Increased alkaline phosphatase | 31 | 1.2 | 26 | 0.3 |
Increased amylase | 30 | 7 | 19 | 1.3 |
Increased AST | 30 | 3.5 | 22 | 0.3 |
Hypomagnesemia | 29 | 1.2 | 33 | 0.6 |
Hypocalcemia | 26 | 1.4 | 22 | 1.8 |
Increased creatinine | 26 | 1.2 | 23 | 0.6 |
Hyperkalemia | 22 | 1.7 | 21 | 2.1 |
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and ipilimumab and platinum-doublet chemotherapy group (range: 197 to 347 patients) and platinum-doublet chemotherapy group (range: 191 to 335 patients).
Second-line Treatment of Metastatic NSCLC
Tables 19 and 20 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-057.
Table 19: Adverse Reactions Occurring in ³10% of OPDIVO-Treated Patients and at a Higher Incidence than Docetaxel (Between Arm Difference of ³5% All Grades or ³2% Grades 3-4) - CHECKMATE-017 and CHECKMATE-057 | ||||
Adverse Reaction | OPDIVO | Docetaxel | ||
All | Grades | All | Grades | |
Respiratory, Thoracic and Mediastinal | ||||
Cough | 31 | 0.7 | 24 | 0 |
Metabolism and Nutrition | ||||
Decreased appetite | 28 | 1.4 | 23 | 1.5 |
Skin and Subcutaneous Tissue | ||||
Pruritus | 10 | 0.2 | 2 | 0 |
Toxicity was graded per NCI CTCAE v4.
Other clinically important adverse reactions observed in OPDIVO-treated patients, and which occurred at a similar incidence in docetaxel-treated patients and not listed elsewhere in Special warnings and precautions for use (4.4) include: fatigue/asthenia (48% all Grades, 5% Grade 3-4), musculoskeletal pain (33% all Grades), pleural effusion (4.5% all Grades), pulmonary embolism (3.3% all Grades).
Table 20: Laboratory Abnormalities Worsening from Baselinea Occurring in ³10% of OPDIVO-Treated Patients for all NCI CTCAE Grades and at a Higher Incidence than Docetaxel (Between Arm Difference of ³5% All Grades or ³2% Grades 3-4) - CHECKMATE-017 and CHECKMATE-057 | ||||
Laboratory Abnormality | OPDIVO | Docetaxel | ||
All Grades (%) | Grades 3-4 (%) | All Grades (%) | Grades 3-4 (%) | |
Chemistry |
|
|
|
|
Hyponatremia | 35 | 7 | 34 | 4.9 |
Increased AST | 27 | 1.9 | 13 | 0.8 |
Increased alkaline phosphatase | 26 | 0.7 | 18 | 0.8 |
Increased ALT | 22 | 1.7 | 17 | 0.5 |
Increased creatinine | 18 | 0 | 12 | 0.5 |
Increased TSHb | 14 | N/A | 6 | N/A |
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 405 to 417 patients) and docetaxel group (range: 372 to 390 patients), except for TSH: OPDIVO group n=314 and docetaxel group n=297.
b Not graded per NCI CTCAE v4.
Malignant Pleural Mesothelioma
Tables 21 and 22 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-743.
Table 21: Adverse Reactions in ≥10% of Patients Receiving OPDIVO and Ipilimumab - CHECKMATE-743 | ||||
Adverse Reaction | OPDIVO and Ipilimumab | Chemotherapy | ||
All Grades | Grades 3-4 | All Grades | Grades 3-4 | |
General | ||||
Fatiguea | 43 | 4.3 | 45 | 6 |
Pyrexiab | 18 | 1.3 | 4.6 | 0.7 |
Edemac | 17 | 0 | 8 | 0 |
Musculoskeletal and Connective Tissue | ||||
Musculoskeletal paind | 38 | 3.3 | 17 | 1.1 |
Arthralgia | 13 | 1 | 1.1 | 0 |
Skin and Subcutaneous Tissue | ||||
Rashe | 34 | 2.7 | 11 | 0.4 |
Pruritusf | 21 | 1 | 1.4 | 0 |
Gastrointestinal | ||||
Diarrheag | 32 | 6 | 12 | 1.1 |
Nausea | 24 | 0.7 | 43 | 2.5 |
Constipation | 19 | 0.3 | 30 | 0.7 |
Abdominal painh | 15 | 1 | 10 | 0.7 |
Vomiting | 14 | 0 | 18 | 2.1 |
Respiratory, Thoracic, and Mediastinal | ||||
Dyspneai | 27 | 2.3 | 16 | 3.2 |
Coughj | 23 | 0.7 | 9 | 0 |
Metabolism and Nutrition | ||||
Decreased appetite | 24 | 1 | 25 | 1.4 |
Endocrine | ||||
Hypothyroidismk | 15 | 0 | 1.4 | 0 |
Infections and Infestations | ||||
Upper respiratory tract infectionl | 12 | 0.3 | 7 | 0 |
Pneumoniam | 10 | 4 | 4.2 | 2.1 |
a Includes fatigue and asthenia.
b Includes pyrexia and tumor-associated fever.
c Includes edema, generalized edema, peripheral edema, and peripheral swelling.
d Includes musculoskeletal pain, back pain, bone pain, flank pain, involuntary muscle contractions, muscle spasms, muscle twitching, musculoskeletal chest pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, polymyalgia rheumatica, and spinal pain.
e Includes rash, acne, acneiform dermatitis, allergic dermatitis, atopic dermatitis, autoimmune dermatitis, bullous dermatitis, contact dermatitis, dermatitis, drug eruption, dyshidrotic eczema, eczema, erythematous rash, exfoliative rash, generalized exfoliative dermatitis, generalized rash, granulomatous dermatitis, keratoderma blennorrhagica, macular rash, maculopapular rash, morbilliform rash, nodular rash, papular rash, psoriasiform dermatitis, pruritic rash, pustular rash, skin exfoliation, skin reaction, skin toxicity, Stevens-Johnson syndrome, toxic skin eruption, and urticaria.
f Includes pruritus, allergic pruritus, and generalized pruritus.
g Includes diarrhea, colitis, enteritis, infectious enteritis, enterocolitis, infectious enterocolitis, microscopic colitis, ulcerative colitis, and viral enterocolitis.
h Includes abdominal pain, abdominal discomfort, abdominal tenderness, gastrointestinal pain, lower abdominal pain, and upper abdominal pain.
i Includes dyspnea, dyspnea at rest, and exertional dyspnea.
j Includes cough, productive cough, and upper-airway cough syndrome.
k Includes hypothyroidism, autoimmune thyroiditis, decreased free tri-iodothyronine, increased blood thyroid stimulating hormone, primary hypothyroidism, thyroiditis, and autoimmune hypothyroidism.
l Includes upper respiratory tract infection, nasopharyngitis, pharyngitis, and rhinitis.
m Includes pneumonia, lower respiratory tract infection, lung infection, aspiration pneumonia, and Pneumocystis jirovecii pneumonia.
Table 22: Laboratory Values Worsening from Baselinea Occurring in ≥20% of Patients on OPDIVO and Ipilimumab - CHECKMATE-743 | ||||
Laboratory Abnormality | OPDIVO and Ipilimumab | Chemotherapy | ||
Grades 1-4 | Grades 3-4 | Grades 1-4 | Grades 3-4 | |
Chemistry | ||||
Hyperglycemia | 53 | 3.7 | 34 | 1.1 |
Increased AST | 38 | 7 | 17 | 0 |
Increased ALT | 37 | 7 | 15 | 0.4 |
Increased lipase | 34 | 13 | 9 | 0.8 |
Hyponatremia | 32 | 8 | 21 | 2.9 |
Increased alkaline phosphatase | 31 | 3.1 | 12 | 0 |
Hyperkalemia | 30 | 4.1 | 16 | 0.7 |
Hypocalcemia | 28 | 0 | 16 | 0 |
Increased amylase | 26 | 5 | 13 | 0.9 |
Increased creatinine | 20 | 0.3 | 20 | 0.4 |
Hematology | ||||
Lymphopenia | 43 | 8 | 57 | 14 |
Anemia | 43 | 2.4 | 75 | 15 |
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and ipilimumab group (range: 109 to 297 patients) and chemotherapy group (range: 90 to 276 patients).
Advanced Renal Cell Carcinoma
First-line Renal Cell Carcinoma
CHECKMATE-214
Tables 23 and 24 summarize adverse reactions and laboratory abnormalities, respectively, that occurred in >15% of OPDIVO and ipilimumab‑treated patients in CHECKMATE-214.
Table 23: Adverse Reactions in >15% of Patients Receiving OPDIVO and Ipilimumab - CHECKMATE-214 | ||||
Adverse Reaction | OPDIVO and Ipilimumab | Sunitinib | ||
Grades 1-4 (%) | Grades 3-4 (%) | Grades 1-4 (%) | Grades 3-4 (%) | |
Adverse Reaction | 99 | 65 | 99 | 76 |
General | ||||
Fatiguea | 58 | 8 | 69 | 13 |
Pyrexia | 25 | 0.7 | 17 | 0.6 |
Edemab | 16 | 0.5 | 17 | 0.6 |
Skin and Subcutaneous Tissue | ||||
Rashc | 39 | 3.7 | 25 | 1.1 |
Pruritus/generalized pruritus | 33 | 0.5 | 11 | 0 |
Gastrointestinal |
|
|
|
|
Diarrhea | 38 | 4.6 | 58 | 6 |
Nausea | 30 | 2 | 43 | 1.5 |
Vomiting | 20 | 0.9 | 28 | 2.1 |
Abdominal pain | 19 | 1.6 | 24 | 1.9 |
Constipation | 17 | 0.4 | 18 | 0 |
Musculoskeletal and Connective Tissue | ||||
Musculoskeletal paind | 37 | 4 | 40 | 2.6 |
Arthralgia | 23 | 1.3 | 16 | 0 |
Respiratory, Thoracic and Mediastinal | ||||
Cough/productive cough | 28 | 0.2 | 25 | 0.4 |
Dyspnea/exertional dyspnea | 20 | 2.4 | 21 | 2.1 |
Metabolism and Nutrition | ||||
Decreased appetite | 21 | 1.8 | 29 | 0.9 |
Nervous System | ||||
Headache | 19 | 0.9 | 23 | 0.9 |
Endocrine | ||||
Hypothyroidism | 18 | 0.4 | 27 | 0.2 |
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia.
b Includes peripheral edema, peripheral swelling.
c Includes dermatitis described as acneiform, bullous, and exfoliative, drug eruption, rash described as exfoliative, erythematous, follicular, generalized, macular, maculopapular, papular, pruritic, and pustular, fixed-drug eruption.
d Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain.
Table 24: Laboratory Values Worsening from Baselinea Occurring in >15% of Patients on OPDIVO and Ipilimumab - CHECKMATE‑214 | ||||
Laboratory Abnormality | OPDIVO and Ipilimumab | Sunitinib | ||
Grades 1-4 (%) | Grades 3-4 (%) | Grades 1-4 (%) | Grades 3-4 (%) | |
Chemistry |
|
|
|
|
Increased lipase | 48 | 20 | 51 | 20 |
Increased creatinine | 42 | 2.1 | 46 | 1.7 |
Increased ALT | 41 | 7 | 44 | 2.7 |
Increased AST | 40 | 4.8 | 60 | 2.1 |
Increased amylase | 39 | 12 | 33 | 7 |
Hyponatremia | 39 | 10 | 36 | 7 |
Increased alkaline phosphatase | 29 | 2 | 32 | 1 |
Hyperkalemia | 29 | 2.4 | 28 | 2.9 |
Hypocalcemia | 21 | 0.4 | 35 | 0.6 |
Hypomagnesemia | 16 | 0.4 | 26 | 1.6 |
Hematology | ||||
Anemia | 43 | 3 | 64 | 9 |
Lymphopenia | 36 | 5 | 63 | 14 |
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and ipilimumab group (range: 490 to 538 patients) and sunitinib group (range: 485 to 523 patients).
In addition, among patients with TSH ≤ULN at baseline, a lower proportion of patients experienced a treatment-emergent elevation of TSH > ULN in the OPDIVO and ipilimumab group compared to the sunitinib group (31% and 61%, respectively).
CHECKMATE-9ER
Tables 25 and 26 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9ER.
Table 25: Adverse Reactions in >15% of Patients Receiving OPDIVO and Cabozantinib - CHECKMATE-9ER | |||||||
Adverse Reaction | OPDIVO and Cabozantinib | Sunitinib | |||||
Grades 1-4 (%) | Grades 3-4 (%) | Grades 1-4 (%) | Grades 3-4 (%) | ||||
Gastrointestinal | |||||||
Diarrhea | 64 | 7 | 47 | 4.4 | |||
Nausea | 27 | 0.6 | 31 | 0.3 | |||
Abdominal paina | 22 | 1.9 | 15 | 0.3 | |||
Vomiting | 17 | 1.9 | 21 | 0.3 | |||
Dyspepsiab | 15 | 0 | 22 | 0.3 | |||
General | |||||||
Fatiguec | 51 | 8 | 50 | 8 | |||
Hepatobiliary | |||||||
Hepatotoxicityd | 44 | 11 | 26 | 5 | |||
Skin and Subcutaneous Tissue | |||||||
Palmar-plantar erythrodysesthesia syndrome | 40 | 8 | 41 | 8 | |||
Stomatitise | 37 | 3.4 | 46 | 4.4 | |||
Rashf | 36 | 3.1 | 14 | 0 | |||
Pruritus | 19 | 0.3 | 4.4 | 0 | |||
Vascular | |||||||
Hypertensiong | 36 | 13 | 39 | 14 | |||
Endocrine | |||||||
Hypothyroidismh | 34 | 0.3 | 30 | 0.3 | |||
Musculoskeletal and Connective Tissue | |||||||
Musculoskeletal paini | 33 | 3.8 | 29 | 3.1 | |||
Arthralgia | 18 | 0.3 | 9 | 0.3 | |||
Metabolism and Nutrition | |||||||
Decreased appetite | 28 | 1.9 | 20 | 1.3 | |||
Nervous System | |||||||
Dysgeusia | 24 | 0 | 22 | 0 | |||
Headache | 16 | 0 | 12 | 0.6 | |||
Respiratory, Thoracic and Mediastinal | |||||||
Coughj | 20 | 0.3 | 17 | 0 | |||
Dysphonia | 17 | 0.3 | 3.4 | 0 | |||
Infections and Infestations | |||||||
Upper respiratory tract infectionk | 20 | 0.3 | 8 | 0.3 | |||
Toxicity was graded per NCI CTCAE v4.
a Includes abdominal discomfort, abdominal pain lower, abdominal pain upper.
b Includes gastroesophageal reflux disease.
c Includes asthenia.
d Includes hepatotoxicity, ALT increased, AST increased, blood alkaline phosphatase increased, gamma-glutamyl transferase increased, autoimmune hepatitis, blood bilirubin increased, drug induced liver injury, hepatic enzyme increased, hepatitis, hyperbilirubinemia, liver function test increased, liver function test abnormal, transaminases increased, hepatic failure.
e Includes mucosal inflammation, aphthous ulcer, mouth ulceration.
f Includes dermatitis, dermatitis acneiform, dermatitis bullous, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic.
g Includes blood pressure increased, blood pressure systolic increased.
h Includes primary hypothyroidism.
i Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain.
j Includes productive cough.
k Includes nasopharyngitis, pharyngitis, rhinitis.
Table 26: Laboratory Values Worsening from Baselinea Occurring in >20% of Patients on OPDIVO and Cabozantinib - CHECKMATE‑9ER | ||||
Laboratory Abnormality | OPDIVO and Cabozantinib | Sunitinib | ||
Grades 1-4 (%) | Grades 3-4 (%) | Grades 1-4 (%) | Grades 3-4 (%) | |
Chemistry | ||||
Increased ALT | 79 | 9.8 | 39 | 3.5 |
Increased AST | 77 | 7.9 | 57 | 2.6 |
Hypophosphatemia | 69 | 28 | 48 | 10 |
Hypocalcemia | 54 | 1.9 | 24 | 0.6 |
Hypomagnesemia | 47 | 1.3 | 25 | 0.3 |
Hyperglycemia | 44 | 3.5 | 44 | 1.7 |
Hyponatremia | 43 | 11 | 36 | 12 |
Increased lipase | 41 | 14 | 38 | 13 |
Increased amylase | 41 | 10 | 28 | 6 |
Increased alkaline phosphatase | 41 | 2.8 | 37 | 1.6 |
Increased creatinine | 39 | 1.3 | 42 | 0.6 |
Hyperkalemia | 35 | 4.7 | 27 | 1 |
Hypoglycemia | 26 | 0.8 | 14 | 0.4 |
Hematology | ||||
Lymphopenia | 42 | 6.6 | 45 | 10 |
Thrombocytopenia | 41 | 0.3 | 70 | 9.7 |
Anemia | 37 | 2.5 | 61 | 4.8 |
Leukopenia | 37 | 0.3 | 66 | 5.1 |
Neutropenia | 35 | 3.2 | 67 | 12
|
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and cabozantinib group (range: 170 to 317 patients) and sunitinib group (range: 173 to 311 patients).
Previously Treated Renal Cell Carcinoma
CHECKMATE-025
Tables 27 and 28 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-025.
Table 27: Adverse Reactions in >15% of Patients Receiving OPDIVO - CHECKMATE-025 | ||||
Adverse Reaction | OPDIVO (n=406) | Everolimus (n=397) | ||
Grades 1-4 (%) | Grades 3-4 (%) | Grades 1-4 (%) | Grades 3-4 (%) | |
Adverse Reaction | 98 | 56 | 96 | 62 |
General | ||||
Fatiguea | 56 | 6 | 57 | 7 |
Pyrexia | 17 | 0.7 | 20 | 0.8 |
Respiratory, Thoracic and Mediastinal | ||||
Cough/productive cough | 34 | 0 | 38 | 0.5 |
Dyspnea/exertional dyspnea | 27 | 3 | 31 | 2 |
Upper respiratory infectionb | 18 | 0 | 11 | 0 |
Gastrointestinal | ||||
Nausea | 28 | 0.5 | 29 | 1 |
Diarrheac | 25 | 2.2 | 32 | 1.8 |
Constipation | 23 | 0.5 | 18 | 0.5 |
Vomiting | 16 | 0.5 | 16 | 0.5 |
Skin and Subcutaneous Tissue | ||||
Rashd | 28 | 1.5 | 36 | 1 |
Pruritus/generalized pruritus | 19 | 0 | 14 | 0 |
Metabolism and Nutrition | ||||
Decreased appetite | 23 | 1.2 | 30 | 1.5 |
Musculoskeletal and Connective Tissue | ||||
Arthralgia | 20 | 1 | 14 | 0.5 |
Back pain | 21 | 3.4 | 16 | 2.8 |
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia, decreased activity, fatigue, and malaise.
b Includes nasopharyngitis, pharyngitis, rhinitis, and viral upper respiratory infection (URI).
c Includes colitis, enterocolitis, and gastroenteritis.
d Includes dermatitis, acneiform dermatitis, erythematous rash, generalized rash, macular rash, maculopapular rash, papular rash, pruritic rash, erythema multiforme, and erythema.
Other clinically important adverse reactions in CHECKMATE-025 were:
General Disorders and Administration Site Conditions: peripheral edema/edema
Gastrointestinal Disorders: abdominal pain/discomfort
Musculoskeletal and Connective Tissue Disorders: extremity pain, musculoskeletal pain
Nervous System Disorders: headache/migraine, peripheral neuropathy
Investigations: weight decreased
Skin Disorders: palmar-plantar erythrodysesthesia
Table 28: Laboratory Values Worsening from Baselinea Occurring in >15% of Patients on OPDIVO - CHECKMATE-025
Laboratory Abnormality | OPDIVO | Everolimus | ||
Grades 1-4 (%) | Grades 3-4 (%) | Grades 1-4 (%) | Grades 3-4 (%) | |
Hematology |
|
|
|
|
Lymphopenia | 42 | 6 | 53 | 11 |
Anemia | 39 | 8 | 69 | 16 |
Chemistry |
|
|
|
|
Increased creatinine | 42 | 2 | 45 | 1.6 |
Increased AST | 33 | 2.8 | 39 | 1.6 |
Increased alkaline phosphatase | 32 | 2.3 | 32 | 0.8 |
Hyponatremia | 32 | 7 | 26 | 6 |
Hyperkalemia | 30 | 4 | 20 | 2.1 |
Hypocalcemia | 23 | 0.9 | 26 | 1.3 |
Increased ALT | 22 | 3.2 | 31 | 0.8 |
Hypercalcemia | 19 | 3.2 | 6 | 0.3 |
Lipids |
|
|
|
|
Increased triglycerides | 32 | 1.5 | 67 | 11 |
Increased cholesterol | 21 | 0.3 | 55 | 1.4
|
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 259 to 401 patients) and everolimus group (range: 257 to 376 patients).
Classical Hodgkin Lymphoma
Tables 29 and 30 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-205 and CHECKMATE-039.
Table 29: Adverse Reactions Occurring in ³10% of Patients - CHECKMATE-205 and CHECKMATE-039 |
| ||
Adverse Reactiona | OPDIVO | ||
| |||
| |||
| |||
All Grades (%) | Grades 3-4 (%) |
| |
Infections |
| ||
Upper respiratory tract infectionb | 44 | 0.8 |
|
Pneumonia/bronchopneumoniac | 13 | 3.8 |
|
Nasal congestion | 11 | 0 |
|
General |
| ||
Fatigued | 39 | 1.9 |
|
Pyrexia | 29 | <1 |
|
Respiratory, Thoracic and Mediastinal |
| ||
Cough/productive cough | 36 | 0 |
|
Dyspnea/exertional dyspnea | 15 | 1.5 |
|
Gastrointestinal | |||
Diarrheae | 33 | 1.5 |
|
Nausea | 20 | 0 |
|
Vomiting | 19 | <1 |
|
Abdominal painf | 16 | <1 |
|
Constipation | 14 | 0.4 |
|
Musculoskeletal and Connective Tissue |
| ||
Musculoskeletal paing | 26 | 1.1 |
|
Arthralgia | 16 | <1 |
|
Skin and Subcutaneous Tissue |
| ||
Rashh | 24 | 1.5 |
|
Pruritus | 20 | 0 |
|
Nervous System |
| ||
Headache | 17 | <1 |
|
Neuropathy peripherali | 12 | <1 |
|
Injury, Poisoning and Procedural Complications |
|
|
|
Infusion-related reaction | 14 | <1 |
|
Endocrine |
| ||
Hypothyroidism/thyroiditis | 12 | 0 |
|
Toxicity was graded per NCI CTCAE v4.
a Includes events occurring up to 30 days after last nivolumab dose, regardless of causality. After an immune-mediated adverse reaction, reactions following nivolumab rechallenge were included if they occurred up to 30 days after completing the initial nivolumab course.
b Includes nasopharyngitis, pharyngitis, rhinitis, and sinusitis.
c Includes pneumonia bacterial, pneumonia mycoplasmal, pneumocystis jirovecii pneumonia.
d Includes asthenia.
e Includes colitis.
f Includes abdominal discomfort and upper abdominal pain.
g Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, and pain in extremity.
h Includes dermatitis, dermatitis acneiform, dermatitis exfoliative, and rash described as macular, papular, maculopapular, pruritic, exfoliative, or acneiform.
i Includes hyperesthesia, hypoesthesia, paresthesia, dysesthesia, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy. These numbers are specific to treatment-emergent events.
Additional information regarding clinically important adverse reactions:
Immune-mediated pneumonitis: In CHECKMATE-205 and CHECKMATE-039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO (one Grade 3 and 12 Grade 2). The median time to onset was 4.5 months (range: 5 days to 12 months). All 13 patients received systemic corticosteroids, with resolution in 12. Four patients permanently discontinued OPDIVO due to pneumonitis. Eight patients continued OPDIVO (three after dose delay), of whom two had recurrence of pneumonitis.
Peripheral neuropathy: Treatment-emergent peripheral neuropathy was reported in 12% (31/266) of all patients receiving OPDIVO. Twenty-eight patients (11%) had new-onset peripheral neuropathy and 3 patients had worsening of neuropathy from baseline. The median time to onset was 50 (range: 1 to 309) days.
Complications of allogeneic HSCT after OPDIVO: Of 17 patients with cHL from the CHECKMATE-205 and CHECKMATE-039 trials who underwent allogeneic HSCT after treatment with OPDIVO, 6 patients (35%) died from transplant-related complications. Five deaths occurred in the setting of severe (Grade 3 to 4) or refractory GVHD. Hyperacute GVHD occurred in 2 patients (12%) and Grade 3 or higher GVHD was reported in 5 patients (29%). Hepatic VOD occurred in 1 patient, who received reduced-intensity conditioned allogeneic HSCT and died of GVHD and multi-organ failure.
Table 30 summarizes laboratory abnormalities in patients with cHL. The most common (³20%) treatment-emergent laboratory abnormalities included cytopenias, liver function abnormalities, and increased lipase. Other common findings (³10%) included increased creatinine, electrolyte abnormalities, and increased amylase.
| Table 30: Laboratory Abnormalities Worsening from Baselinea Occurring in ³10% of Patients - CHECKMATE-205 and CHECKMATE-039 | ||
Laboratory Abnormality | OPDIVOa (n=266) | |
All Grades (%)b | Grades 3-4 (%)b | |
Hematology |
|
|
Leukopenia | 38 | 4.5 |
Neutropenia | 37 | 5 |
Thrombocytopenia | 37 | 3 |
Lymphopenia | 32 | 11 |
Anemia | 26 | 2.6 |
Chemistryc |
|
|
Increased AST | 33 | 2.6 |
Increased ALT | 31 | 3.4 |
Increased lipase | 22 | 9 |
Increased alkaline phosphatase | 20 | 1.5 |
Hyponatremia | 20 | 1.1 |
Hypokalemia | 16 | 1.9 |
Increased creatinine | 16 | <1 |
Hypocalcemia | 15 | <1 |
Hyperkalemia | 15 | 1.5 |
Hypomagnesemia | 14 | <1 |
Increased amylase | 13 | 1.5 |
Increased bilirubin | 11 | 1.5 |
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement: range: 203 to 266 patients.
b Includes events occurring up to 30 days after last nivolumab dose. After an immune-mediated adverse reaction, reactions following nivolumab rechallenge were included if they occurred within 30 days of completing the initial nivolumab course.
c In addition, in the safety population, fasting hyperglycemia (all grade 1-2) was reported in 27 of 69 (39%) evaluable patients and fasting hypoglycemia (all grade 1-2) in 11 of 69 (16%).
Urothelial Carcinoma
Adjuvant Treatment of Urothelial Carcinoma (UC)
Tables 31 and 32 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-274.
Table 31: Adverse Reactions Occurring in ³10% of Patients - CHECKMATE‑274 | ||||
Adverse Reaction | OPDIVO (n=351) | Placebo (n=348) | ||
All Grades (%) | Grades 3-4 (%) | All Grades (%) | Grades 3-4 (%) | |
Skin and Subcutaneous Tissue | ||||
Rasha | 36 | 1.7 | 19 | 0.3 |
Pruritus | 30 | 0 | 16 | 0 |
General | ||||
Fatigue/Asthenia | 36 | 1.1 | 32 | 0.3 |
Pyrexia | 10 | 0.3 | 10 | 0.3 |
Gastrointestinal | ||||
Diarrheab | 30 | 2.8 | 27 | 1.7 |
Nausea | 16 | 0.6 | 13 | 0 |
Abdominal painc | 15 | 0.9 | 15 | 0.6 |
Constipation | 13 | 0.3 | 15 | 0.3 |
Musculoskeletal and Connective Tissue | ||||
Musculoskeletal paind | 28 | 0.6 | 24 | 0.9 |
Arthralgia | 11 | 0.3 | 13 | 0 |
Infections | ||||
Urinary tract infectione | 22 | 6 | 23 | 9 |
Upper respiratory tract infectionf | 16 | 0.3 | 16 | 0.6 |
Endocrine | ||||
Hyperthyroidism | 11 | 0 | 1.1 | 0 |
Hypothyroidism | 11 | 0 | 2.3 | 0 |
Renal and Urinary Disorders | ||||
Renal dysfunctiong | 17 | 1.7 | 16 | 0.9 |
Respiratory, Thoracic and Mediastinal | ||||
Coughh | 14 | 0 | 11 | 0 |
Dyspneai | 11 | 0.3 | 6 | 0.3 |
Metabolism and Nutrition | ||||
Decreased appetite | 13 | 0.9 | 7 | 0.3 |
Nervous System Disorders | ||||
Dizzinessj | 11 | 0.3 | 9 | 0 |
Hepatobiliary | ||||
Hepatitisk | 11 | 4 | 8 | 0.6 |
Toxicity was graded per NCI CTCAE v4.
a Includes acne, blister, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis contact, eczema, eczema asteatotic, eczema nummular, erythema, erythema multiforme, lichen sclerosus, lichenoid keratosis, pemphigoid, photosensitivity reaction, pigmentation disorder, psoriasis, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rosacea, skin exfoliation, skin lesion, skin reaction, toxic skin eruption, and urticaria.
b Includes colitis, colitis microscopic, diarrhea, duodenitis, enteritis, immune-mediated enterocolitis
c Includes abdominal pain, abdominal discomfort, abdominal tenderness, lower and upper abdominal pain.
d Includes musculoskeletal pain, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain.
e Includes cystitis, escherichia urinary tract infection, pyelonephritis, pyelonephritis acute, pyelonephritis chronic, urethritis, urinary tract infection, urinary tract infection bacterial, urinary tract infection staphylococcal, and urosepsis.
f Includes upper respiratory tract infection, nasopharyngitis, pharyngitis and rhinitis.
g Includes acute kidney injury, autoimmune nephritis, blood creatinine increased, glomerular filtration rate decreased, immune-mediated nephritis, nephritis, renal failure, and renal impairment.
h Includes cough, productive cough, and upper-airway cough syndrome.
i Includes dyspnea and exertional dyspnea.
j Includes dizziness, postural dizziness and vertigo.
k Includes aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubin increased, cholangitis, drug-induced liver injury, hepatic failure, hepatic function abnormal, hepatitis, hepatocellular injury, hyperbilirubinemia, gamma-glutamyl transferase increased, liver injury, and transaminases increased.
Table 32: Laboratory Abnormalities Worsening from Baselinea Occurring in ³10% of Patients - CHECKMATE-274
Laboratory Abnormality | OPDIVO (n=351) | Placebo (n=348) | ||
All Grades (%) | Grades 3-4 (%) | All Grades (%) | Grades 3-4 (%) | |
Chemistry | ||||
Increased creatinine | 36 | 1.7 | 36 | 2.6 |
Increased amylase | 34 | 8 | 23 | 3.2 |
Increased lipase | 33 | 12 | 31 | 10 |
Hyperkalemia | 32 | 5 | 30 | 6 |
Increased alkaline phosphatase | 24 | 2.3 | 15 | 0.6 |
Increased AST | 24 | 3.5 | 16 | 0.9 |
Increased ALT | 23 | 2.9 | 15 | 0.6 |
Hyponatremia | 22 | 4.1 | 17 | 1.8 |
Hypocalcemia | 17 | 1.2 | 11 | 0.9 |
Hypomagnesemia | 16 | 0 | 9 | 0 |
Hypercalcemia | 12 | 0.3 | 8 | 0.3 |
Hematology | ||||
Lymphopenia | 33 | 2.9 | 27 | 1.5 |
Anemia | 30 | 1.4 | 28 | 0.9 |
Neutropenia | 11 | 0.6 | 10 | 0.3 |
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 322 to 348 patients) and placebo group (range: 312 to 341 patients).
First-line Treatment of Unresectable or Metastatic UC
Tables 33 and 34 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-901.
Table 33: Adverse Reactions Occurring in ≥10% of Treated Patients - CHECKMATE‑901 | ||||||||
Adverse Reaction | OPDIVO and Platinum-Doublet Chemotherapy | Platinum-Doublet Chemotherapy (n=288) | ||||||
All Grades (%) | Grades 3-4 (%) | All Grades (%) | Grades 3-4 (%) | |||||
Gastrointestinal disorders | ||||||||
Nausea | 52 | 0.3 | 53 | 1 | ||||
Constipation | 30 | 0 | 28 | 0.7 | ||||
Vomiting | 23 | 1.3 | 19 | 2.1 | ||||
Diarrheaa | 19 | 2 | 14 | 0 | ||||
Abdominal painb | 14 | 0.3 | 9 | 0.3 | ||||
General | ||||||||
Fatiguec | 48 | 3.9 | 43 | 4.2 | ||||
Edemad | 18 | 0 | 9 | 0.3 | ||||
Pyrexiae | 14 | 1 | 14 | 0 | ||||
Musculoskeletal and Connective Tissue | ||||||||
Musculoskeletal painf | 33 | 3 | 21 | 0.3 | ||||
Metabolism and Nutrition | ||||||||
Decreased appetite | 30 | 1.6 | 19 | 1 | ||||
Skin and Subcutaneous Tissue | ||||||||
Rashg | 25 | 2.3 | 7 | 0.3 | ||||
Pruritus | 17 | 0.7 | 3.5 | 0 | ||||
Nervous System Disorders |
|
|
|
| ||||
Peripheral neuropathyh | 20 | 0.7 | 14 | 0 | ||||
Headachei | 11 | 0 | 5 | 0 | ||||
Infections | ||||||||
Urinary tract infectionj | 19 | 8 | 18 | 8 | ||||
Endocrine disorders |
|
|
|
| ||||
Hypothyroidismk | 17 | 0 | 0.3 | 0 | ||||
Renal and Urinary Disorders |
|
|
|
| ||||
Renal dysfunctionl | 14 | 6 | 11 | 1.7 | ||||
Hematuria | 11 | 1 | 7 | 1.4 | ||||
Investigations |
|
|
|
| ||||
Weight decreased | 11 | 0.3 | 6 | 0 | ||||
Toxicity was graded per NCI CTCAE v4.
a Includes colitis, immune-mediated enterocolitis.
b Includes upper abdominal pain, lower abdominal pain, abdominal discomfort, epigastric discomfort, gastrointestinal pain, and hepatic pain.
c Includes asthenia.
d Includes peripheral edema, swelling, peripheral swelling, localized edema, swelling, face edema, testicular edema, gravitational edema, and edema genital.
e Includes hyperthermia, body temperature increased and hyperpyrexia.
f Includes back pain, arthralgia, bone pain, arthritis, musculoskeletal chest pain, non-cardiac chest pain, myalgia, neck pain, pain in extremity, and spinal pain.
g Includes maculopapular rash, erythematous rash, macular rash, papular rash, pustular rash, acneiform dermatitis, dermatitis, allergic dermatitis, atopic dermatitis, exfoliative rash, eczema asteatotic, erythema multiforme, palmar-plantar erythrodysesthesia syndrome, eczema, dermatitis exfoliative generalized, and skin exfoliation.
h Includes paresthesia, peripheral sensory neuropathy, hypoesthesia, dysesthesia, neuralgia, hyperesthesia, peripheral motor neuropathy, polyneuropathy.
i Includes occipital neuralgia.
j Includes urosepsis, cystitis, pyelonephritis, pyelonephritis acute, urinary tract infection enterococcal, escherichia urinary tract infection.
k Includes blood stimulating hormone increased.
l Includes acute kidney injury, renal failure, renal impairment, glomerular filtration rate decreased, anuria, azotemia.
Table 34: Selected Laboratory Abnormalities Worsening from Baselinea Occurring in ≥20% of Patients - CHECKMATE-901 |
| ||||
Laboratory Abnormality | OPDIVO and Platinum-Doublet Chemotherapy | Platinium-Doublet Chemotherapy |
| ||
Grades 1-4 (%) | Grades 3-4 (%) | Grades 1-4 (%) | Grades 3-4 (%) |
| |
Hematology |
| ||||
Anemia | 88 | 21 | 80 | 21 |
|
Neutropenia | 82 | 35 | 76 | 28 |
|
Lymphopenia | 71 | 17 | 56 | 13 | |
Thrombocytopenia | 60 | 13 | 51 | 8 |
|
Chemistry |
| ||||
Increased creatinine | 53 | 2.4 | 42 | 1.1 |
|
Hypomagnesemia | 48 | 3.8 | 39 | 1.5 |
|
Hyponatremia | 43 | 13 | 39 | 8 |
|
Hyperglycemia | 41 | 3.9 | 37 | 3.2 |
|
Hypocalcemia | 36 | 2.1 | 24 | 1.1 |
|
Hyperkalemia | 33 | 3.0 | 32 | 1.1 |
|
Increased amylase | 32 | 4.2 | 23 | 3.6 |
|
Increased AST | 31 | 2.4 | 17 | 0.7 |
|
Increased ALT | 29 | 2.4 | 19 | 0.7 |
|
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 289-301 patients) and chemotherapy group (range: 265-281 patients).
Previously Treated Advanced or Metastatic UC
Tables 35 and 36 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-275.
| Table 35: Adverse Reactions Occurring in ≥10% of Patients - CHECKMATE-275 | ||
Adverse Reaction | OPDIVO (n=270) | |
All Grades (%) | Grades 3-4 (%) | |
99 | 51 | |
General | ||
Asthenia/fatigue/malaise | 46 | 7 |
Pyrexia/tumor associated fever | 17 | 0.4 |
Edema/peripheral edema/peripheral swelling | 13 | 0.4 |
Musculoskeletal and Connective Tissue | ||
Musculoskeletal paina | 30 | 2.6 |
Arthralgia | 10 | 0.7 |
Metabolism and Nutrition | ||
Decreased appetite | 22 | 2.2 |
Gastrointestinal | ||
Nausea | 22 | 0.7 |
Diarrhea | 17 | 2.6 |
Constipation | 16 | 0.4 |
Abdominal painb | 13 | 1.5 |
Vomiting | 12 | 1.9 |
Respiratory, Thoracic and Mediastinal |
|
|
Cough/productive cough | 18 | 0 |
Dyspnea/exertional dyspnea | 14 | 3.3 |
Infections | ||
Urinary tract infection/escherichia/fungal urinary tract infection | 17 | 7 |
Skin and Subcutaneous Tissue
| ||
Rashc | 16 | 1.5 |
Pruritus | 12 | 0 |
Endocrine | ||
Thyroid disordersd | 15 | 0 |
Toxicity was graded per NCI CTCAE v4.
a Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain.
b Includes abdominal discomfort, lower and upper abdominal pain.
c Includes dermatitis, dermatitis acneiform, dermatitis bullous, and rash described as generalized, macular, maculopapular, or pruritic.
d Includes autoimmune thyroiditis, blood TSH decrease, blood TSH increase, hyperthyroidism, hypothyroidism, thyroiditis, thyroxine decreased, thyroxine free increased, thyroxine increased, tri-iodothyronine free increased, tri-iodothyronine increased.
| Table 36: Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Patients - CHECKMATE-275 | ||
Laboratory Abnormality | OPDIVOa | |
All Grades (%) | Grades 3-4 (%) | |
Chemistry |
|
|
Hyperglycemia | 42 | 2.4 |
Hyponatremia | 41 | 11 |
Increased creatinine | 39 | 2 |
Increased alkaline phosphatase | 33 | 5.5 |
Hypocalcemia | 26 | 0.8 |
Increased AST | 24 | 3.5 |
Increased lipase | 20 | 7 |
Hyperkalemia | 19 | 1.2 |
Increased ALT | 18 | 1.2 |
Increased amylase | 18 | 4.4 |
Hypomagnesemia | 16 | 0 |
Hematology | ||
Lymphopenia | 42 | 9 |
Anemia | 40 | 7 |
Thrombocytopenia | 15 | 2.4 |
Leukopenia | 11 | 0 |
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: range: 84 to 256 patients.
Esophageal Cancer
Adjuvant Treatment of Resected Esophageal or Gastroesophageal Junction Cancer
Tables 37 and 38 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-577.
Table 37: Adverse Reactions Occurring in ³10% of Patients Receiving OPDIVO - CHECKMATE-577 | ||||
Adverse Reaction | OPDIVO (n=532) | Placebo (n=260) | ||
All Grades (%) | Grades 3-4 (%) | All Grades (%) | Grades 3-4 (%) | |
96 | 34 | 93 | 32 | |
Gastrointestinal | ||||
Diarrhea | 29 | 0.9 | 29 | 0.8 |
Nausea | 23 | 0.8 | 21 | 0 |
Abdominal Paina | 17 | 0.8 | 20 | 1.5 |
Vomiting | 15 | 0.6 | 16 | 1.2 |
Dysphagia | 13 | 0.8 | 17 | 3.5 |
Dyspepsiab | 12 | 0.2 | 16 | 0.4 |
Constipation | 11 | 0 | 12 | 0 |
General | ||||
Fatiguec | 34 | 1.3 | 29 | 1.5 |
Respiratory, Thoracic and Mediastinal | ||||
Coughd | 20 | 0.2 | 21 | 0.4 |
Dyspneae | 12 | 0.8 | 12 | 0.4 |
Skin and Subcutaneous Tissue | ||||
Rashf | 21 | 0.9 | 10 | 0.4 |
Pruritus | 13 | 0.4 | 6 | 0 |
Investigations | ||||
Weight decreased | 13 | 0.4 | 9 | 0 |
Musculoskeletal and Connective Tissue | ||||
Musculoskeletal paing | 21 | 0.6 | 20 | 0.8 |
Arthralgia | 10 | 0.2 | 8 | 0 |
Metabolism and Nutrition | ||||
Decreased appetite | 15 | 0.9 | 10 | 0.8 |
Endocrine | ||||
Hypothyroidism | 11 | 0 | 1.5 | 0 |
a Includes upper abdominal pain, lower abdominal pain, and abdominal discomfort.
b Includes gastroesophageal reflux.
c Includes asthenia.
d Includes productive cough.
e Includes dyspnea exertional.
f Includes rash pustular, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, exfoliative rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic.
g Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, myalgia intercostal, neck pain, pain in extremity, spinal pain.
Table 38: Laboratory Abnormalities Worsening from Baselinea Occurring in ³10% of Patients - CHECKMATE-577 | ||||
Laboratory Abnormality | OPDIVO (n=532) | Placebo (n=260) | ||
All Grades (%) | Grades 3-4 (%) | All Grades (%) | Grades 3-4 (%) | |
Chemistry | ||||
Increased AST | 27 | 2.1 | 22 | 0.8 |
Increased alkaline phosphatase | 25 | 0.8 | 18 | 0.8 |
Increased albumin | 21 | 0.2 | 18 | 0 |
Increased ALT | 20 | 1.9 | 16 | 1.2 |
Increased amylase | 20 | 3.9 | 13 | 1.3 |
Hyponatremia | 19 | 1.7 | 12 | 1.2 |
Hyperkalemia | 17 | 0.8 | 15 | 1.6 |
Hypokalemia | 12 | 1 | 11 | 1.2 |
Transaminases increasedb | 11 | 1.5 | 6 | 1.2 |
Hematology | ||||
Lymphopenia | 44 | 17 | 35 | 12 |
Anemia | 27 | 0.8 | 21 | 0.4 |
Neutropenia | 24 | 1.5 | 23 | 0.4 |
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 163 to 526 patients) and Placebo group (range: 86 to 256 patients).
b Includes alanine aminotransferase increased, aspartate aminotransferase increased.
First-line Treatment of Unresectable Advanced or Metastatic ESCC
Tables 39 and 40 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-648.
Table 39: Adverse Reactions in ≥10% of Patients - CHECKMATE-648 | ||||||
Adverse Reaction | OPDIVO with Cisplatin and 5‑FU (n=310) | OPDIVO and Ipilimumab (n=322) | Cisplatin and 5-FU | |||
All Grades (%) | Grades 3-4 (%) | All Grades (%) | Grades 3-4 (%) | All Grades (%) | Grades 3-4 (%) | |
Gastrointestinal | ||||||
Nausea | 65 | 4.2 | 22 | 0.6 | 56 | 2.6 |
Constipation | 44 | 1 | 20 | 0.3 | 43 | 1 |
Stomatitisa | 44 | 9 | 11 | 0.6 | 35 | 3 |
Diarrhea | 29 | 2.9 | 22 | 1.9 | 20 | 2 |
Vomiting | 23 | 2.3 | 15 | 1.6 | 19 | 3 |
Dysphagia | 14 | 7 | 12 | 5 | 12 | 4.9 |
Abdominal painb | 13 | 1.9 | 10 | 0.9 | 11 | 0.7 |
Metabolism and Nutrition | ||||||
Decreased appetite | 51 | 7 | 17 | 4 | 50 | 6 |
General | ||||||
Fatiguec | 47 | 3.5 | 28 | 2.5 | 41 | 4.9 |
Pyrexiad | 19 | 0.3 | 23 | 0.9 | 12 | 0.3 |
Edemae | 16 | 0 | 7 | 0 | 13 | 0 |
Nervous System | ||||||
Peripheral neuropathyf | 18 | 1.3 | 2.8 | 0 | 13 | 1 |
Psychiatric | ||||||
Insomnia | 16 | 0 | 8 | 0 | 10 | 0.3 |
Skin and Subcutaneous Tissue | ||||||
Rashg | 16 | 0.6 | 31 | 3.1 | 7 | 0 |
Pruritus | 11 | 0 | 17 | 0.9 | 3.6 | 0 |
Alopecia | 10 | 0 |
|
| 11 | 0 |
Respiratory, Thoracic and Mediastinal | ||||||
Coughh | 16 | 0.3 | 13 | 0.3 | 13 | 0.3 |
Infections and Infestations | ||||||
Pneumoniai | 13 | 5 | 14 | 8 | 10 | 2.6 |
Endocrine | ||||||
Hypothyroidism | 7 | 0 | 14 | 0 | 0.3 | 0 |
Investigations | ||||||
Weight decreased | 12 | 0.6 | 12 | 1.9 | 11 | 1 |
Musculoskeletal and Connective Tissue | ||||||
Musculoskeletal painj | 11 | 0.3 | 14 | 0.6 | 8 | 0.3 |
Toxicity was graded per NCI CTCAE v4.
a Includes aphthous ulcer, mouth ulceration, and mucosal inflammation.
b Includes abdominal discomfort, abdominal pain lower, and abdominal pain upper.
c Includes asthenia and malaise.
d Includes tumor associated fever.
e Includes swelling, generalized edema, edema peripheral, and peripheral swelling.
f Includes hyperesthesia, hypoesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, and peripheral sensory neuropathy.
g Includes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, drug eruption, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, and rash pruritic.
h Includes productive cough.
i Includes organizing pneumonia, pneumonia bacterial, and pneumonia pseudomonal.
j Includes back pain, bone pain, musculoskeletal chest pain, myalgia, neck pain, pain in extremity, and spinal pain.
Table 40: Laboratory Values Worsening from Baselinea Occurring in ≥10% of Patients - CHECKMATE-648 | ||||||
Laboratory Abnormality | OPDIVO with Cisplatin and 5‑FU | OPDIVO and Ipilimumab (n=322) | Cisplatin and 5-FU | |||
Grades 1-4 (%) | Grades 3-4 (%) | Grades 1-4 (%) | Grades 3-4 (%) | Grades 1-4 (%) | Grades 3-4 (%) | |
Hematology | ||||||
Anemia | 81 | 21 | 52 | 7 | 66 | 14 |
Lymphopenia | 67 | 23 | 50 | 13 | 44 | 8 |
Neutropenia | 61 | 18 | 13 | 1.3 | 48 | 13 |
Leukopenia | 53 | 11 |
|
| 39 | 5 |
Thrombocytopenia | 43 | 3.3 | 12 | 1 | 29 | 2.8 |
Chemistry | ||||||
Hyponatremia | 52 | 15 | 45 | 11 | 40 | 8 |
Hypocalcemia | 43 | 3 | 32 | 0 | 23 | 0.7 |
Increased creatinine | 41 | 2.3 | 15 | 0.7 | 31 | 0.7 |
Hypomagnesemia | 35 | 1.7 | 15 | 0 | 25 | 1.8 |
Hyperglycemia | 34 | 0 | 43 | 4.3 | 36 | 0.8 |
Hyperkalemia | 33 | 2.3 | 23 | 1.6 | 24 | 0.7 |
Hypokalemia | 29 | 9 | 19 | 5 | 17 | 6 |
Increased alkaline phosphatase | 26 | 1.3 | 31 | 3.3 | 15 | 0 |
Increased AST | 23 | 3.3 | 39 | 6 | 11 | 1.4 |
Increased ALT | 23 | 2.3 | 33 | 6 | 8 | 0.7 |
Hypoglycemia | 18 | 0.4 | 15 | 1.2 | 7 | 0 |
Hypercalcemia | 11 | 2.6 | 15 | 2 | 8 | 0 |
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO with cisplatin and 5-FU group (range: 60 to 305 patients), OPDIVO and ipilimumab group (range: 59 to 307 patients) or cisplatin and 5-FU group (range: 56 to 283 patients).
Previously-Treated Unresectable Advanced, Recurrent or Metastatic Esophageal Squamous Cell Carcinoma (ESCC)
Tables 41 and 42 summarize the adverse reactions and laboratory abnormalities, respectively, in ATTRACTION-3.
Table 41: Adverse Reactions Occurring in ³10% of Patients Receiving OPDIVO - ATTRACTION-3 | ||||
Adverse Reaction | OPDIVO (n=209) | Docetaxel or Paclitaxel (n=208) | ||
All Grades (%) | Grades 3-4 (%) | All Grades (%) | Grades 3-4 (%) | |
Skin and Subcutaneous Tissue | ||||
Rasha | 22 | 1.9 | 28 | 1 |
Pruritus | 12 | 0 | 7 | 0 |
Metabolism and Nutrition | ||||
Decreased appetiteb | 21 | 1.9 | 35 | 5 |
Gastrointestinal | ||||
Diarrheac | 18 | 1.9 | 17 | 1.4 |
Constipation | 17 | 0 | 19 | 0 |
Nausea | 11 | 0 | 20 | 0.5 |
Musculoskeletal and Connective Tissue | ||||
Musculoskeletal paind | 17 | 0 | 26 | 1.4 |
Infections | ||||
Upper respiratory tract infectione | 17 | 1 | 14 | 0 |
Pneumoniaf | 13 | 5 | 19 | 9 |
Respiratory, Thoracic and Mediastinal | ||||
Coughg | 16 | 0 | 14 | 0.5 |
General | ||||
Pyrexiah | 16 | 0.5 | 19 | 0.5 |
Fatiguei | 12 | 1.4 | 27 | 4.8 |
Blood and Lymphatic System | ||||
Anemiaj | 13 | 8 | 30 | 13 |
Endocrine | ||||
Hypothyroidismk | 11 | 0 | 1.4 | 0 |
Toxicity was graded per NCI CTCAE v4.
a Includes urticaria, drug eruption, eczema, eczema asteatotic, eczema nummular, palmar-plantar erythrodysesthesia syndrome, erythema, erythema multiforme, blister, skin exfoliation, Stevens-Johnson syndrome, dermatitis, dermatitis described as acneiform, bullous, or contact, and rash described as maculo-papular, generalized, or pustular.
b Includes hypophagia, and food aversion.
c Includes colitis.
d Includes spondylolisthesis, periarthritis, musculoskeletal chest pain, neck pain, arthralgia, back pain, myalgia, pain in extremity, arthritis, bone pain, and periarthritis calcarea.
e Includes influenza, influenza like illness, pharyngitis, nasopharyngitis, tracheitis, and bronchitis and upper respiratory infection with bronchitis.
f Includes pneumonia aspiration, pneumonia bacterial, and lung infection. Two patients (1.0%) died of pneumonia in the OPDIVO treatment arm. Two patients (1.0%) died of pneumonia in the chemotherapy treatment arm; these deaths occurred with paclitaxel only.
g Includes productive cough.
h Includes tumor-associated fever.
i Includes asthenia.
j Includes hemoglobin decreased, and iron deficiency anemia.
k Includes blood thyroid stimulating hormone increased.
Table 42: Laboratory Abnormalities Worsening from Baselinea Occurring in ³10% of Patients - ATTRACTION-3 | ||||
Laboratory Abnormality | OPDIVO (n=209) | Docetaxel or Paclitaxel (n=208) | ||
All Grades (%) | Grades 3-4 (%) | All Grades (%) | Grades 3-4 (%) | |
Chemistry | ||||
Increased creatinine | 78 | 0.5 | 68 | 0.5 |
Hyperglycemia | 52 | 5 | 62 | 5 |
Hyponatremia | 42 | 11 | 50 | 12 |
Increased AST | 40 | 6 | 30 | 1 |
Increased alkaline phosphatase | 33 | 4.8 | 24 | 1 |
Increased ALT | 31 | 5 | 22 | 1.9 |
Hypercalcemia | 22 | 6 | 14 | 2.9 |
Hyperkalemia | 22 | 0.5 | 31 | 1 |
Hypoglycemia | 14 | 1.4 | 14 | 0.5 |
Hypokalemia | 11 | 2.9 | 13 | 3.4 |
Hematology | ||||
Lymphopenia | 46 | 19 | 72 | 43 |
Anemia | 42 | 9 | 71 | 17 |
Leukopenia | 11 | 0.5 | 79 | 45 |
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (209 patients) and Docetaxel or Paclitaxel group (range: 207 to 208 patients).
Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma
Tables 43 and 44 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-649.
Table 43: Adverse Reactions in ≥10% of Patients Receiving OPDIVO and Chemotherapy - CHECKMATE-649 | ||||
Adverse Reaction | OPDIVO and mFOLFOX6 or CapeOX (n=782) | mFOLFOX6 or CapeOX | ||
All Grades (%) | Grades 3-4 (%) | All Grades (%) | Grades 3-4 (%) | |
Adverse Reaction | 99 | 69 | 98 | 59 |
Nervous System | ||||
Peripheral neuropathya | 53 | 7 | 46 | 4.8 |
Headache | 11 | 0.8 | 6 | 0.3 |
Gastrointestinal | ||||
Nausea | 48 | 3.2 | 44 | 3.7 |
Diarrhea | 39 | 5 | 34 | 3.7 |
Vomiting | 31 | 4.2 | 29 | 4.2 |
Abdominal painb | 27 | 2.8 | 24 | 2.6 |
Constipation | 25 | 0.6 | 21 | 0.4 |
Stomatitisc | 17 | 1.8 | 13 | 0.8 |
General | ||||
Fatigued | 44 | 7 | 40 | 5 |
Pyrexiae | 19 | 1 | 11 | 0.4 |
Edemaf | 12 | 0.5 | 8 | 0.1 |
Metabolism and Nutrition | ||||
Decreased appetite | 29 | 3.6 | 26 | 2.5 |
Hypoalbuminemiag | 14 | 0.3 | 9 | 0.3 |
Investigations | ||||
Weight decreased | 17 | 1.3 | 15 | 0.7 |
Increased lipase | 14 | 7 | 8 | 3.7 |
Increased amylase | 12 | 3.1 | 5 | 0.4 |
Musculoskeletal and Connective Tissue | ||||
Musculoskeletal painh | 20 | 1.3 | 14 | 2 |
Skin and Subcutaneous Tissue | ||||
Rashi | 18 | 1.7 | 4.4 | 0.1 |
Palmar-plantar erythrodysesthesia syndrome | 13 | 1.5 | 12 | 0.8 |
Respiratory, Thoracic and Mediastinal | ||||
Coughj | 13 | 0.1 | 9 | 0 |
Infections and Infestations | ||||
Upper respiratory tract infectionk | 10 | 0.1 | 7 | 0.1 |
Toxicity was graded per NCI CTCAE v4.
a Includes dysesthesia, hypoesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, and peripheral sensory neuropathy.
b Includes abdominal discomfort, abdominal pain lower, and abdominal pain upper.
c Includes aphthous ulcer, mouth ulceration, and mucosal inflammation.
d Includes asthenia.
e Includes tumor associated fever.
f Includes swelling, generalized edema, edema peripheral, and peripheral swelling.
g Includes blood albumin decreased.
h Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain.
i Includes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, drug eruption, exfoliative rash, nodular rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash vesicular.
j Includes productive cough.
k Includes nasopharyngitis, pharyngitis, and rhinitis.
Table 44: Laboratory Values Worsening from Baselinea Occurring in ≥10% of Patients - CHECKMATE-649 | ||||
Laboratory Abnormality | OPDIVO and mFOLFOX6 or CapeOX | mFOLFOX6 or CapeOX | ||
Grades 1-4 (%) | Grades 3-4 (%) | Grades 1-4 (%) | Grades 3-4 (%) | |
Hematology | ||||
Neutropenia | 73 | 29 | 62 | 23 |
Leukopenia | 69 | 12 | 59 | 9 |
Thrombocytopenia | 68 | 7 | 63 | 4.4 |
Anemia | 59 | 14 | 60 | 10 |
Lymphopenia | 59 | 12 | 49 | 9 |
Chemistry | ||||
Increased AST | 52 | 4.6 | 47 | 1.9 |
Hypocalcemia | 42 | 1.6 | 37 | 1 |
Hyperglycemia | 41 | 3.9 | 38 | 2.7 |
Increased ALT | 37 | 3.4 | 30 | 1.9 |
Hyponatremia | 34 | 6 | 24 | 5 |
Hypokalemia | 27 | 7 | 24 | 4.8 |
Hyperbilirubinemia | 24 | 2.8 | 21 | 2 |
Increased creatinine | 15 | 1 | 9 | 0.5 |
Hyperkalemia | 14 | 1.4 | 11 | 0.7 |
Hypoglycemia | 12 | 0.7 | 9 | 0.2 |
Hypernatremia | 11 | 0.5 | 7.1 | 0 |
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and mFOLFOX6 or CapeOX group (407 to 767 patients) or mFOLFOX6 or CapeOX group (range: 405 to 735 patients).
Description of selected adverse reactions
Immune-Mediated Pneumonitis
OPDIVO as a Single Agent
Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients receiving OPDIVO as a single agent, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%) adverse reactions. Pneumonitis led to permanent discontinuation of OPDIVO in 1.1% and withholding of OPDIVO in 0.8% of patients.
Systemic corticosteroids were required in 100% (61/61) of patients with pneumonitis. Pneumonitis resolved in 84% of the 61 patients. Of the 15 patients in whom OPDIVO was withheld for pneumonitis, 14 reinitiated OPDIVO after symptom improvement; of these, 4 (29%) had recurrence of pneumonitis.
OPDIVO with Ipilimumab
OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg:
In NSCLC, immune-mediated pneumonitis occurred in 9% (50/576) of patients receiving OPDIVO 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4.0%) immune-mediated pneumonitis. Four patients (0.7%) died due to pneumonitis. Immune-mediated pneumonitis led to permanent discontinuation of OPDIVO with ipilimumab in 5% of patients and withholding of OPDIVO with ipilimumab in 3.6% of patients.
Systemic corticosteroids were required in 100% of patients with pneumonitis. Pneumonitis resolved in 72% of the patients. Approximately 13% (2/16) of patients had recurrence of pneumonitis after reinitiation of OPDIVO with ipilimumab.
Immune-Mediated Colitis
OPDIVO as a Single Agent
Immune-mediated colitis occurred in 2.9% (58/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (1.7%) and Grade 2 (1%) adverse reactions. Colitis led to permanent discontinuation of OPDIVO in 0.7% and withholding of OPDIVO in 0.9% of patients.
Systemic corticosteroids were required in 100% (58/58) of patients with colitis. Four patients required addition of infliximab to high-dose corticosteroids. Colitis resolved in 86% of the 58 patients. Of the 18 patients in whom OPDIVO was withheld for colitis, 16 reinitiated OPDIVO after symptom improvement; of these, 12 (75%) had recurrence of colitis.
OPDIVO with Ipilimumab
OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg:
Immune-mediated colitis occurred in 25% (115/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 4 (0.4%), Grade 3 (14%), and Grade 2 (8%) adverse reactions. Colitis led to permanent discontinuation of OPDIVO with ipilimumab in 14% and withholding of OPDIVO with ipilimumab in 4.4% of patients.
Systemic corticosteroids were required in 100% (115/115) of patients with colitis. Approximately 23% of patients required addition of infliximab to high-dose corticosteroids. Colitis resolved in 93% of the 115 patients. Of the 20 patients in whom OPDIVO with ipilimumab was withheld for colitis, 16 reinitiated treatment after symptom improvement; of these, 9 (56%) had recurrence of colitis.
OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg:
Immune-mediated colitis occurred in 9% (60/666) of patients with RCC or CRC receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (4.4%) and Grade 2 (3.7%) adverse reactions. Colitis led to permanent discontinuation of OPDIVO with ipilimumab in 3.2% and withholding of OPDIVO with ipilimumab in 2.7% of patients with RCC or CRC.
Systemic corticosteroids were required in 100% (60/60) of patients with colitis. Approximately 23% of patients with immune-mediated colitis required addition of infliximab to high-dose corticosteroids. Colitis resolved in 95% of the 60 patients. Of the 18 patients in whom OPDIVO with ipilimumab was withheld for colitis, 16 reinitiated treatment after symptom improvement; of these, 10 (63%) had recurrence of colitis.
Immune-Mediated Hepatitis and Hepatotoxicity
OPDIVO as a Single Agent
Immune-mediated hepatitis occurred in 1.8% (35/1994) of patients receiving OPDIVO as a single agent, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%) adverse reactions. Hepatitis led to permanent discontinuation of OPDIVO in 0.7% and withholding of OPDIVO in 0.6% of patients.
Systemic corticosteroids were required in 100% (35/35) of patients with hepatitis. Two patients required the addition of mycophenolic acid to high-dose corticosteroids. Hepatitis resolved in 91% of the 35 patients. Of the 12 patients in whom OPDIVO was withheld for hepatitis, 11 reinitiated OPDIVO after symptom improvement; of these, 9 (82%) had recurrence of hepatitis.
OPDIVO with Ipilimumab
OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg:
Immune-mediated hepatitis occurred in 15% (70/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%) adverse reactions. Immune-mediated hepatitis led to permanent discontinuation of OPDIVO with ipilimumab in 8% or withholding of OPDIVO with ipilimumab in 3.5% of patients.
Systemic corticosteroids were required in 100% (70/70) of patients with hepatitis. Approximately 9% of patients with immune-mediated hepatitis required the addition of mycophenolic acid to high-dose corticosteroids. Hepatitis resolved in 91% of the 70 patients. Of the 16 patients in whom OPDIVO with ipilimumab was withheld for hepatitis, 14 reinitiated treatment after symptom improvement; of these, 8 (57%) had recurrence of hepatitis.
OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg:
Immune-mediated hepatitis occurred in 7% (48/666) of patients with RCC or CRC receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 4 (1.2%), Grade 3 (4.9%), and Grade 2 (0.4%) adverse reactions. Immune-mediated hepatitis led to permanent discontinuation of OPDIVO with ipilimumab in 3.6% and withholding of OPDIVO with ipilimumab in 2.6% of patients with RCC or CRC.
Systemic corticosteroids were required in 100% (48/48) of patients with hepatitis. Approximately 19% of patients with immune-mediated hepatitis required addition of mycophenolic acid to high-dose corticosteroids. Hepatitis resolved in 88% of the 48 patients. Of the 17 patients in whom OPDIVO with ipilimumab was withheld for hepatitis, 14 reinitiated treatment after symptom improvement; of these, 10 (71%) had recurrence of hepatitis.
OPDIVO with Cabozantinib
OPDIVO in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade 3 and 4 ALT and AST elevations compared to OPDIVO alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt OPDIVO and cabozantinib and consider administering corticosteroids [see Posology and method of administration (4.2)].
With the combination of OPDIVO and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% of patients [see Undesirable effects (4.8)]. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either OPDIVO (n=11) or cabozantinib (n=9) administered as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving OPDIVO, 2 patients receiving cabozantinib, and 7 patients receiving both OPDIVO and cabozantinib.
Immune-Mediated Endocrinopathies
Adrenal Insufficiency
OPDIVO as a Single Agent
Adrenal insufficiency occurred in 1% (20/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (0.4%) and Grade 2 (0.6%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO in 0.1% and withholding of OPDIVO in 0.4% of patients.
Approximately 85% of patients with adrenal insufficiency received hormone replacement therapy. Systemic corticosteroids were required in 90% (18/20) of patients with adrenal insufficiency. Adrenal insufficiency resolved in 35% of the 20 patients. Of the 8 patients in whom OPDIVO was withheld for adrenal insufficiency, 4 reinitiated OPDIVO after symptom improvement and all required hormone replacement therapy for their ongoing adrenal insufficiency.
OPDIVO with Ipilimumab
OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg:
Adrenal insufficiency occurred in 8% (35/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO with ipilimumab in 0.4% and withholding of OPDIVO with ipilimumab in 2.0% of patients.
Approximately 71% (25/35) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 37% of the 35 patients. Of the 9 patients in whom OPDIVO with ipilimumab was withheld for adrenal insufficiency, 7 reinitiated treatment after symptom improvement and all required hormone replacement therapy for their ongoing adrenal insufficiency.
OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg:
Adrenal insufficiency occurred in 7% (48/666) of patients with RCC or CRC who received OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO with ipilimumab in 1.2% and withholding of OPDIVO with ipilimumab in 2.1% of patients with RCC or CRC.
Approximately 94% (45/48) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 29% of the 48 patients. Of the 14 patients in whom OPDIVO with ipilimumab was withheld for adrenal insufficiency, 11 reinitiated treatment after symptom improvement; of these, all received hormone replacement therapy and 2 (18%) had recurrence of adrenal insufficiency.
OPDIVO with Cabozantinib
Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received OPDIVO with cabozantinib, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO and cabozantinib in 0.9% and withholding of OPDIVO and cabozantinib in 2.8% of patients with RCC.
Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom OPDIVO with cabozantinib was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.
Hypophysitis
OPDIVO as a Single Agent
Hypophysitis occurred in 0.6% (12/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (0.2%) and Grade 2 (0.3%) adverse reactions. Hypophysitis led to permanent discontinuation of OPDIVO in <0.1% and withholding of OPDIVO in 0.2% of patients.
Approximately 67% (8/12) of patients with hypophysitis received hormone replacement therapy, including systemic corticosteroids. Hypophysitis resolved in 42% of the 12 patients. Of the 3 patients in whom OPDIVO was withheld for hypophysitis, 2 reinitiated OPDIVO after symptom improvement; of these, none had recurrence of hypophysitis.
OPDIVO with Ipilimumab
OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg:
Hypophysitis occurred in 9% (42/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (2.4%) and Grade 2 (6%) adverse reactions. Hypophysitis led to permanent discontinuation of OPDIVO with ipilimumab in 0.9% and withholding of OPDIVO with ipilimumab in 4.2% of patients.
Approximately 86% of patients with hypophysitis received hormone replacement therapy. Systemic corticosteroids were required in 88% (37/42) of patients with hypophysitis. Hypophysitis resolved in 38% of the 42 patients. Of the 19 patients in whom OPDIVO with ipilimumab was withheld for hypophysitis, 9 reinitiated treatment after symptom improvement; of these, 1 (11%) had recurrence of hypophysitis.
OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg:
Hypophysitis occurred in 4.4% (29/666) of patients with RCC or CRC receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 4 (0.3%), Grade 3 (2.4%), and Grade 2 (0.9%) adverse reactions. Hypophysitis led to permanent discontinuation of OPDIVO with ipilimumab in 1.2% and withholding of OPDIVO with ipilimumab in 2.1% of patients with RCC or CRC.
Approximately 72% (21/29) of patients with hypophysitis received hormone replacement therapy, including systemic corticosteroids. Hypophysitis resolved in 59% of the 29 patients. Of the 14 patients in whom OPDIVO with ipilimumab was withheld for hypophysitis, 11 reinitiated treatment after symptom improvement; of these, 2 (18%) had recurrence of hypophysitis.
Thyroiditis
OPDIVO as a Single Agent
Thyroiditis occurred in 0.6% (12/1994) of patients receiving OPDIVO as a single agent, including Grade 2 (0.2%) adverse reactions. Thyroiditis led to permanent discontinuation of OPDIVO in no patients and withholding of OPDIVO in 0.2% of patients.
Systemic corticosteroids were required in 17% (2/12) of patients with thyroiditis. Thyroiditis resolved in 58% of the 12 patients. Of the 3 patients in whom OPDIVO was withheld for thyroiditis, 1 reinitiated OPDIVO after symptom improvement without recurrence of thyroiditis.
Hyperthyroidism
OPDIVO as a Single Agent
Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (<0.1%) and Grade 2 (1.2%) adverse reactions. Hyperthyroidism led to the permanent discontinuation of OPDIVO in no patients and withholding of OPDIVO in 0.4% of patients.
Approximately 19% of patients with hyperthyroidism received methimazole, 7% received carbimazole, and 4% received propylthiouracil. Systemic corticosteroids were required in 9% (5/54) of patients. Hyperthyroidism resolved in 76% of the 54 patients. Of the 7 patients in whom OPDIVO was withheld for hyperthyroidism, 4 reinitiated OPDIVO after symptom improvement; of these, none had recurrence of hyperthyroidism.
OPDIVO with Ipilimumab
OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg:
Hyperthyroidism occurred in 9% (42/456) of patients with melanoma or HCC who received OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (0.9%) and Grade 2 (4.2%) adverse reactions. Hyperthyroidism led to the permanent discontinuation of OPDIVO with ipilimumab in no patients and withholding of OPDIVO with ipilimumab in 2.4% of patients.
Approximately 26% of patients with hyperthyroidism received methimazole and 21% received carbimazole. Systemic corticosteroids were required in 17% (7/42) of patients. Hyperthyroidism resolved in 91% of the 42 patients. Of the 11 patients in whom OPDIVO with ipilimumab was withheld for hyperthyroidism, 8 reinitiated treatment after symptom improvement; of these, 1 (13%) had recurrence of hyperthyroidism.
OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg:
Hyperthyroidism occurred in 12% (80/666) of patients with RCC or CRC who received OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (0.6%) and Grade 2 (4.5%) adverse reactions. Hyperthyroidism led to permanent discontinuation of OPDIVO with ipilimumab in no patients and withholding of OPDIVO with ipilimumab in 2.3% of patients with RCC or CRC.
Of the 80 patients with RCC or CRC who developed hyperthyroidism, approximately 16% received methimazole and 3% received carbimazole. Systemic corticosteroids were required in 20% (16/80) of patients with hyperthyroidism. Hyperthyroidism resolved in 85% of the 80 patients. Of the 15 patients in whom OPDIVO with ipilimumab was withheld for hyperthyroidism, 11 reinitiated treatment after symptom improvement; of these, 3 (27%) had recurrence of hyperthyroidism.
Hypothyroidism
OPDIVO as a Single Agent
Hypothyroidism occurred in 8% (163/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (0.2%) and Grade 2 (4.8%) adverse reactions. Hypothyroidism led to the permanent discontinuation of OPDIVO in no patients and withholding of OPDIVO in 0.5% of patients.
Approximately 79% of patients with hypothyroidism received levothyroxine. Systemic corticosteroids were required in 3.1% (5/163) of patients with hypothyroidism. Hypothyroidism resolved in 35% of the 163 patients. Of the 9 patients in whom OPDIVO was withheld for hypothyroidism, 3 reinitiated OPDIVO after symptom improvement; of these, 1 (33%) had recurrence of hypothyroidism.
OPDIVO with Ipilimumab
OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg:
Hypothyroidism occurred in 20% (91/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (0.4%) and Grade 2 (11%) adverse reactions. Hypothyroidism led to the permanent discontinuation of OPDIVO with ipilimumab in 0.9% and withholding of OPDIVO with ipilimumab in 0.9% of patients.
Approximately 89% of patients with hypothyroidism received levothyroxine. Systemic corticosteroids were required in 2.2% (2/91) of patients with hypothyroidism. Hypothyroidism resolved in 41% of the 91 patients. Of the 4 patients in whom OPDIVO with ipilimumab was withheld for hypothyroidism, 2 reinitiated treatment after symptom improvement; of these, none had recurrence of hypothyroidism.
OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg:
Hypothyroidism occurred in 18% (122/666) of patients with RCC or CRC who received OPDIVO 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (0.6%) and Grade 2 (11%) adverse reactions. Hypothyroidism led to permanent discontinuation of OPDIVO with ipilimumab in 0.2% and withholding of OPDIVO with ipilimumab in 1.4% of patients with RCC or CRC.
Of the 122 patients with RCC or CRC who developed hypothyroidism, approximately 82% received levothyroxine. Systemic corticosteroids were required in 7% (9/122) of patients with hypothyroidism. Hypothyroidism resolved in 27% of the 122 patients. Of the 9 patients in whom OPDIVO with ipilimumab was withheld for hypothyroidism, 5 reinitiated treatment after symptom improvement; of these, 1 (20%) had recurrence of hypothyroidism.
Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis
OPDIVO as a Single Agent
Diabetes occurred in 0.9% (17/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (0.4%) and Grade 2 (0.3%) adverse reactions, and two cases of diabetic ketoacidosis. Diabetes led to the permanent discontinuation of OPDIVO in no patients and withholding of OPDIVO in 0.1% of patients.
No patients (0/17) with diabetes required systemic corticosteroids. Diabetes resolved in 29% of the 17 patients. Of the 2 patients in whom OPDIVO was withheld for diabetes, both reinitiated OPDIVO after symptom improvement; of these, neither had recurrence of diabetes.
Immune-Mediated Nephritis with Renal Dysfunction
OPDIVO as a Single Agent
Immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients receiving OPDIVO as a single agent, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%) adverse reactions. Immune-mediated nephritis and renal dysfunction led to permanent discontinuation of OPDIVO in 0.3% and withholding of OPDIVO in 0.4% of patients.
Systemic corticosteroids were required in 100% (23/23) of patients with nephritis and renal dysfunction. Nephritis and renal dysfunction resolved in 78% of the 23 patients. Of the 7 patients in whom OPDIVO was withheld for nephritis or renal dysfunction, 7 reinitiated OPDIVO after symptom improvement; of these, 1 (14%) had recurrence of nephritis or renal dysfunction.
Immune-Mediated Dermatologic Adverse Reactions
OPDIVO as a Single Agent
Immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%) adverse reactions. Immune-mediated rash led to permanent discontinuation of OPDIVO in 0.3% and withholding of OPDIVO in 0.5% of patients.
Systemic corticosteroids were required in 100% (171/171) of patients with immune-mediated rash. Rash resolved in 72% of the 171 patients. Of the 10 patients in whom OPDIVO was withheld for immune-mediated rash, 9 reinitiated OPDIVO after symptom improvement; of these, 3 (33%) had recurrence of immune-mediated rash.
OPDIVO with Ipilimumab
OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg:
Immune-mediated rash occurred in 28% (127/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (4.8%) and Grade 2 (10%) adverse reactions. Immune-mediated rash led to permanent discontinuation of OPDIVO with ipilimumab in 0.4% and withholding of OPDIVO with ipilimumab in 3.9% of patients.
Systemic corticosteroids were required in 100% (127/127) of patients with immune-mediated rash. Rash resolved in 84% of the 127 patients. Of the 18 patients in whom OPDIVO with ipilimumab was withheld for immune-mediated rash, 15 reinitiated treatment after symptom improvement; of these, 8 (53%) had recurrence of immune-mediated rash.
OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg:
Immune-mediated rash occurred in 16% (108/666) of patients with RCC or CRC who received OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (3.5%) and Grade 2 (4.2%) adverse reactions. Immune-mediated rash led to permanent discontinuation of OPDIVO with ipilimumab in 0.5% of patients and withholding of OPDIVO with ipilimumab in 2.0% of patients with RCC or CRC.
Systemic corticosteroids were required in 100% (108/108) of patients with immune-mediated rash. Rash resolved in 75% of the 108 patients. Of the 13 patients in whom OPDIVO with ipilimumab was withheld for immune-mediated rash, 11 reinitiated treatment after symptom improvement; of these, 5 (46%) had recurrence of immune-mediated rash.
Other Immune-Mediated Adverse Reactions
The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO or OPDIVO in combination with ipilimumab or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions.
Cardiac/Vascular: Myocarditis, pericarditis, vasculitis
Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy
Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss
Gastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis
Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatic
Endocrine: Hypoparathyroidism
Other (Hematologic/Immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection
Infusion-Related Reactions
OPDIVO as a Single Agent
In patients who received OPDIVO as a 60-minute intravenous infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients.
In a trial assessing the pharmacokinetics and safety of a more rapid infusion, in which patients received OPDIVO as a 60-minute intravenous infusion or a 30-minute intravenous infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation, or withholding of OPDIVO.
OPDIVO with Ipilimumab
OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg:
Infusion-related reactions occurred in 2.5% (10/407) of patients with melanoma receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks.
OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg:
Infusion-related reactions occurred in 5.1% (28/547) of patients with RCC receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, respectively. Infusion-related reactions occurred in 12% (37/300) of patients with malignant pleural mesothelioma who received OPDIVO 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks.
Pediatric population
See Interaction with other medicinal products and other forms of interaction (4.5).
Other special populations
See Interaction with other medicinal products and other forms of interaction (4.5) and Fertility, pregnancy and lactation (4.6).
4.8.3 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of OPDIVO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Immune system disorders: hypersensitivity
Cardiac disorders: tachycardia, pericardial disorders (includes pericarditis, pericardial effusion, cardiac
tamponade, and Dressler’s syndrome), atrial fibrillation.
Eye: Vogt-Koyanagi-Harada (VKH) syndrome
Complications of OPDIVO Treatment After Allogeneic HSCT: Treatment refractory, severe acute and chronic GVHD
Blood and lymphatic system disorders: Hemophagocytic lymphohistiocytosis (HLH) (including fatal cases), autoimmune hemolytic anemia (including fatal cases)
Nervous System: encephalitis and aseptic meningitis
- To report any side effect(s):
· Saudi Arabia:
Please report adverse drug events to: The National Pharmacovigilance Centre (NPC): SFDA Call Center: 19999 E-mail: npc.drug@sfda.gov.sa Website: https://ade.sfda.gov.sa |
· Other GCC States:
| Please contact the relevant competent authority. |
No cases of overdose have been reported in clinical trials. In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted immediately.
There are no clinically significant exposure-response relationships for efficacy or safety for nivolumab monotherapy across the approved dosing regimens, regardless of cancer type.
Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies and antibody drug conjugates, PD‑1/PDL‑1 (Programmed cell death protein 1/ death ligand 1) inhibitors.
ATC code: L01FF01
Mechanism of Action:
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T-cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.
Combined nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) mediated inhibition results in enhanced T-cell function that is greater than the effects of either antibody alone, and results in improved anti-tumor responses in metastatic melanoma and advanced RCC. In murine syngeneic tumor models, dual blockade of PD-1 and CTLA-4 resulted in increased anti-tumor activity.
Pharmacodynamic effects:
Immunogenicity
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of OPDIVO or of other nivolumab products.
Anti-drug antibody and neutralizing antibody responses were monitored throughout the treatment period where the benefit to risk ratio was assessed. Incidence of anti-drug antibodies and neutralizing antibodies are presented in Table 45.
Table 45: OPDIVO Anti-Drug Antibody (ADA) and Neutralizing Antibody (NAb) Incidence | |||
Treatment Regimena | Indication(s) | ADA | NAbb |
OPDIVO as a single agent | Multiplec | 11% (229/2,085) | 7% (15/229) |
OPDIVO with ipilimumab for 4 doses followed by OPDIVO as a single agent | Melanoma | 38% (149/394) | 12% (18/149) |
HCC | 56% (27/48) | 41% (11/27) | |
RCC and CRC | 26% (132/516) | 3% (4/132) | |
OPDIVO with ipilimumab | Malignant Pleural Mesothelioma | 26% (69/269) | 2.9% (2/69) |
NSCLC | 37% (180/491) | 3.9% (7/180) | |
OPDIVO with ipilimumab and 2 cycles of platinum-doublet chemotherapy | NSCLC | 34% (104/308) | 8% (8/104) |
a Details of each treatment regimen are described in Section 5.1 [see Pharmacodynamic properties (5.1)].
b NAb incidence is reported among the subset of patients positive for ADA.
c Includes unresectable or metastatic melanoma, metastatic NSCLC, advanced RCC, cHL, recurrent or metastatic SCCHN, and UC indications.
ADA = treatment-emergent anti-nivolumab antibodies, NAb = neutralizing antibodies, HCC = hepatocellular carcinoma, RCC = renal cell carcinoma, CRC = colorectal cancer, NSCLC = non-small cell lung cancer.
Effects of Anti-Drug Antibodies
Presence of treatment-emergent anti-nivolumab antibodies increased nivolumab clearance by up to 20% after administration of nivolumab as monotherapy or in combination with ipilimumab. These anti-drug antibody-associated pharmacokinetic changes were not considered to be clinically significant. There was no identified clinically significant effect of anti-drug antibodies on incidence of infusion-related reactions. The effects of anti-drug antibodies on effectiveness have not been fully characterized.
Clinical efficacy and safety:
Unresectable or Metastatic Melanoma
Previously Treated Metastatic Melanoma
CHECKMATE-037 was a multicenter, open-label trial that randomized (2:1) patients with unresectable or metastatic melanoma to receive OPDIVO 3 mg/kg intravenously every 2 weeks or investigator’s choice of chemotherapy, either single-agent dacarbazine 1000 mg/m2 every 3 weeks or the combination of carboplatin AUC 6 intravenously every 3 weeks and paclitaxel 175 mg/m2 intravenously every 3 weeks. Patients were required to have progression of disease on or following ipilimumab treatment and, if BRAF V600 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, medical conditions requiring systemic immunosuppression, ocular melanoma, active brain metastasis, or a history of Grade 4 ipilimumab-related adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the initiating event. Tumor assessments were conducted 9 weeks after randomization then every 6 weeks for the first year, and every 12 weeks thereafter.
Efficacy was evaluated in a single-arm, non-comparative, planned interim analysis of the first 120 patients who received OPDIVO in CHECKMATE-037 and in whom the minimum duration of follow-up was 6 months. The major efficacy outcome measures in this population were confirmed overall response rate (ORR) as measured by blinded independent central review using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and duration of response.
Among the 120 patients treated with OPDIVO, the median age was 58 years (range: 25 to 88), 65% of patients were male, 98% were White, and the ECOG performance score was 0 (58%) or 1 (42%). Disease characteristics were M1c disease (76%), BRAF V600 mutation positive (22%), elevated LDH (56%), history of brain metastases (18%), and two or more prior systemic therapies for metastatic disease (68%).
The ORR was 32% (95% confidence interval [CI]: 23, 41), consisting of 4 complete responses and 34 partial responses in OPDIVO-treated patients. Of 38 patients with responses, 87% had ongoing responses with durations ranging from 2.6+ to 10+ months, which included 13 patients with ongoing responses of 6 months or longer.
There were responses in patients with and without BRAF V600 mutation-positive melanoma. A total of 405 patients were randomized and the median duration of OS was 15.7 months (95% CI: 12.9, 19.9) in OPDIVO-treated patients compared to 14.4 months (95% CI: 11.7, 18.2) (HR 0.95; 95.54% CI: 0.73, 1.24) in patients assigned to investigator’s choice of treatment. Figure 1 summarizes the OS results.
Figure 1: Overall Survival - CHECKMATE-037*
* The primary OS analysis was not adjusted to account for subsequent therapies, with 54 (40.6%) patients in the chemotherapy arm subsequently receiving an anti-PD1 treatment. OS may be confounded by dropout, imbalance of subsequent therapies, and differences in baseline factors.
Previously Untreated Metastatic Melanoma
CHECKMATE-066
CHECKMATE-066 was a multicenter, double-blind, randomized (1:1) trial in 418 patients with BRAF V600 wild-type unresectable or metastatic melanoma. Patients were randomized to receive either OPDIVO 3 mg/kg by intravenous infusion every 2 weeks or dacarbazine 1000 mg/m2 intravenously every 3 weeks until disease progression or unacceptable toxicity. Randomization was stratified by PD-L1 status (³5% of tumor cell membrane staining by immunohistochemistry vs. <5% or indeterminate result) and M stage (M0/M1a/M1b versus M1c). Key eligibility criteria included histologically confirmed, unresectable or metastatic, cutaneous, mucosal, or acral melanoma; no prior therapy for metastatic disease; completion of prior adjuvant or neoadjuvant therapy at least 6 weeks prior to randomization; ECOG performance status 0 or 1; absence of autoimmune disease; and absence of active brain or leptomeningeal metastases. The trial excluded patients with ocular melanoma. Tumor assessments were conducted 9 weeks after randomization then every 6 weeks for the first year and then every 12 weeks thereafter. The major efficacy outcome measure was overall survival (OS). Additional outcome measures included investigator-assessed progression-free survival (PFS) and ORR per RECIST v1.1.
The trial population characteristics were: median age was 65 years (range: 18 to 87), 59% were male, and 99.5% were White. Disease characteristics were M1c stage disease (61%), cutaneous melanoma (74%), mucosal melanoma (11%), elevated LDH level (37%), PD-L1 ³5% tumor cell membrane expression (35%), and history of brain metastasis (4%). More patients in the OPDIVO arm had an ECOG performance status of 0 (71% vs. 58%).
CHECKMATE-066 demonstrated a statistically significant improvement in OS for the OPDIVO arm compared with the dacarbazine arm in an interim analysis based on 47% of the total planned events for OS. At the time of analysis, 88% (63/72) of OPDIVO-treated patients had ongoing responses, which included 43 patients with ongoing response of 6 months or longer. Efficacy results are shown in Table 46 and Figure 2.
Table 46: Efficacy Results - CHECKMATE-066 | ||
| OPDIVO | Dacarbazine |
Overall Survival |
|
|
Deaths (%) | 50 (24) | 96 (46) |
Median (months) (95% CI) | NRa | 10.8 (9.3, 12.1) |
Hazard ratio (95% CI)b | 0.42 (0.30, 0.60) | |
p-valuec,d | <0.0001 | |
Progression-free Survival |
|
|
Disease progression or death (%) | 108 (51) | 163 (78) |
Median (months) (95% CI) | 5.1 (3.5, 10.8) | 2.2 (2.1, 2.4) |
Hazard ratio (95% CI)b | 0.43 (0.34, 0.56) | |
p-valuec,d | <0.0001 | |
Overall Response Rate | 34% | 9% |
(95% CI) | (28, 41) | (5, 13) |
Complete response rate | 4% | 1% |
Partial response rate | 30% | 8% |
a Not Reached.
b Based on a stratified proportional hazards model.
c Based on stratified log-rank test.
d p-value is compared with the allocated alpha of 0.0021 for this interim analysis.
Figure 2: Overall Survival - CHECKMATE-066
CHECKMATE-067
CHECKMATE-067 was a multicenter, randomized (1:1:1), double-blind trial in 945 patients with previously untreated, unresectable or metastatic melanoma to one of the following arms: OPDIVO and ipilimumab, OPDIVO, or ipilimumab. Patients were required to have completed adjuvant or neoadjuvant treatment at least 6 weeks prior to randomization and have no prior treatment with anti-CTLA-4 antibody and no evidence of active brain metastasis, ocular melanoma, autoimmune disease, or medical conditions requiring systemic immunosuppression.
Patients were randomized to receive:
· OPDIVO 1 mg/kg with ipilimumab 3 mg/kg intravenously every 3 weeks for 4 doses, followed by OPDIVO as a single agent at a dose of 3 mg/kg by intravenous infusion every 2 weeks (OPDIVO and ipilimumab arm),
· OPDIVO 3 mg/kg by intravenous infusion every 2 weeks (OPDIVO arm), or
· Ipilimumab 3 mg/kg intravenously every 3 weeks for 4 doses, followed by placebo every 2 weeks (ipilimumab arm).
Randomization was stratified by PD-L1 expression (³5% vs. <5% tumor cell membrane expression) as determined by a clinical trial assay, BRAF V600 mutation status, and M stage per the AJCC staging system (M0, M1a, M1b vs. M1c). Tumor assessments were conducted 12 weeks after randomization then every 6 weeks for the first year, and every 12 weeks thereafter. The major efficacy outcome measures were investigator-assessed PFS per RECIST v1.1 and OS. Additional efficacy outcome measures were confirmed ORR and duration of response.
The trial population characteristics were: median age 61 years (range: 18 to 90); 65% male; 97% White; ECOG performance score 0 (73%) or 1 (27%). Disease characteristics were: AJCC Stage IV disease (93%); M1c disease (58%); elevated LDH (36%); history of brain metastases (4%); BRAF V600 mutation-positive melanoma (32%); PD-L1 ³5% tumor cell membrane expression as determined by the clinical trials assay (46%); and prior adjuvant therapy (22%).
CHECKMATE-067 demonstrated statistically significant improvements in OS and PFS for patients randomized to either OPDIVO-containing arm as compared with the ipilimumab arm. The trial was not designed to assess whether adding ipilimumab to OPDIVO improves PFS or OS compared to OPDIVO as a single agent. Efficacy results are shown in Table 47 and Figure 3.
Table 47: Efficacy Results in CHECKMATE-067 | |||
| OPDIVO and |
|
|
Overall Survivala |
|
|
|
Deaths (%) | 128 (41) | 142 (45) | 197 (63) |
Hazard ratiob (vs. ipilimumab) (95% CI) | 0.55 (0.44, 0.69) | 0.63 (0.50, 0.78) |
|
p-valuec, d | <0.0001 | <0.0001 |
|
Progression-free Survivala |
|
|
|
Disease progression or death | 151 (48%) | 174 (55%) | 234 (74%) |
Median (months) (95% CI) | 11.5 | 6.9 | 2.9 |
Hazard ratiob (vs. ipilimumab) (95% CI) | 0.42 (0.34, 0.51) | 0.57 (0.47, 0.69) |
|
p-valuec, e | <0.0001 | <0.0001 |
|
Confirmed Overall Response Ratea | 50% | 40% | 14% |
(95% CI) | (44, 55) | (34, 46) | (10, 18) |
p-valuef | <0.0001 | <0.0001 |
|
Complete response | 8.9% | 8.5% | 1.9% |
Partial response | 41% | 31% | 12% |
Duration of Response |
|
|
|
Proportion ³6 months in duration | 76% | 74% | 63% |
Range (months) | 1.2+ to 15.8+ | 1.3+ to 14.6+ | 1.0+ to 13.8+ |
a OS results are based on final OS analysis with 28 months of minimum follow-up; PFS (co-primary endpoint) and ORR (secondary endpoint) results were based on primary analysis with 9 months of minimum follow-up.
b Based on a stratified proportional hazards model.
c Based on stratified log-rank test.
d If the maximum of the two OS p-values is less than 0.04 (a significance level assigned by the Hochberg procedure), then both p-values are considered significant.
e p-value is compared with .005 of the allocated alpha for final PFS treatment comparisons.
f Based on the stratified Cochran-Mantel-Haenszel test.
+ Censored observation.
Figure 3: Overall Survival - CHECKMATE-067
Based on a minimum follow-up of 48 months, the median OS was not reached (95% CI: 38.2, NR) in the OPDIVO and ipilimumab arm. The median OS was 36.9 months (95% CI: 28.3, NR) in the OPDIVO arm and 19.9 months (95% CI: 16.9, 24.6) in the ipilimumab arm.
Based on a minimum follow-up of 28 months, the median PFS was 11.7 months (95% CI: 8.9, 21.9) in the OPDIVO and ipilimumab arm, 6.9 months (95% CI: 4.3, 9.5) in the OPDIVO arm, and 2.9 months (95% CI: 2.8, 3.2) in the ipilimumab arm. Based on a minimum follow-up of 28 months, the proportion of responses lasting ≥ 24 months was 55% in the OPDIVO and ipilimumab arm, 56% in the OPDIVO arm, and 39% in the ipilimumab arm.
Adjuvant Treatment of Melanoma
CHECKMATE-76K
CHECKMATE-76K was a randomized, double-blind trial in 790 patients with completely resected Stage IIB/C melanoma. Patients were randomized (2:1) to receive OPDIVO 480 mg or placebo by intravenous infusion every 4 weeks for up to 1 year or until disease recurrence or unacceptable toxicity. Enrollment required complete resection of the primary melanoma with negative margins and a negative sentinel lymph node within 12 weeks prior to randomization, and ECOG performance status of 0 or 1. The trial excluded patients with ocular/uveal or mucosal melanoma, autoimmune disease, any condition requiring systemic treatment with either corticosteroids (≥10 mg daily prednisone or equivalent) or other immunosuppressive medications, as well as patients with prior therapy for melanoma except surgery. Randomization was stratified by AJCC 8th staging system edition (T3b vs. T4a vs. T4b). The major efficacy outcome measure was recurrence-free survival (RFS) defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant metastasis), new primary melanoma, or death, from any cause, whichever occurred first and as assessed by the investigator. Tumor assessments were conducted every 26 weeks during years 1-3 and every 52 weeks thereafter until year 5.
The trial population characteristics were: median age 62 years (range: 19 to 92), 61% were male, 98% were White, 0.4% Black or African American, 0.1% Asian, and 1.1% race unknown, 2.2% Hispanic or Latino, 58% Not Hispanic or Latino, 40% ethnicity unknown, and 94% had an ECOG performance status of 0. Sixty one percent had stage IIB and 39% had stage IIC melanoma.
CHECKMATE-76K demonstrated a statistically significant improvement in RFS for patients randomized to the OPDIVO arm compared with the placebo arm. Efficacy results are shown in Table 48 and Figure 4.
Table 48: Efficacy Results - CHECKMATE-76K | ||
| OPDIVO | Placebo |
Recurrence-free Survival |
|
|
Number of events, n (%) | 66 (13%) | 69 (26%) |
Median (months) b | NRa (28.5, NR) | NRa (21.6, NR) |
Hazard ratioc | 0.42 | |
a Not reached.
b Based on Kaplan-Meier estimates.
c Hazard Ratio is OPDIVO over placebo based on a stratified Cox proportional hazard model.
d Based on a 2-sided stratified log-rank test. Boundary for statistical significance: p‑value <0.033.
Figure 4: Recurrence-free Survival - CHECKMATE-238
CHECKMATE-238
CHECKMATE-238 was a randomized, double-blind trial in 906 patients with completely resected Stage IIIB/C or Stage IV melanoma. Patients were randomized (1:1) to receive OPDIVO 3 mg/kg by intravenous infusion every 2 weeks or ipilimumab 10 mg/kg intravenously every 3 weeks for 4 doses then every 12 weeks beginning at Week 24 for up to 1 year. Enrollment required complete resection of melanoma with margins negative for disease within 12 weeks prior to randomization. The trial excluded patients with a history of ocular/uveal melanoma, autoimmune disease, and any condition requiring systemic treatment with either corticosteroids (≥10 mg daily prednisone or equivalent) or other immunosuppressive medications, as well as patients with prior therapy for melanoma except surgery, adjuvant radiotherapy after neurosurgical resection for lesions of the central nervous system, and prior adjuvant interferon completed ≥6 months prior to randomization. Randomization was stratified by PD-L1 status (positive [based on 5% level] vs. negative/indeterminate) and AJCC stage (Stage IIIB/C vs. Stage IV M1a-M1b vs. Stage IV M1c). The major efficacy outcome measure was recurrence-free survival (RFS) defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant metastasis), new primary melanoma, or death, from any cause, whichever occurs first and as assessed by the investigator. Patients underwent imaging for tumor recurrence every 12 weeks for the first 2 years then every 6 months thereafter.
The trial population characteristics were: median age was 55 years (range: 18 to 86), 58% were male, 95% were White, and 90% had an ECOG performance status of 0. Disease characteristics were AJCC Stage IIIB (34%), Stage IIIC (47%), Stage IV (19%), M1a-b (14%), BRAF V600 mutation positive (42%), BRAF wild-type (45%), elevated LDH (8%), PD-L1 ≥5% tumor cell membrane expression determined by clinical trial assay (34%), macroscopic lymph nodes (48%), and tumor ulceration (32%).
CHECKMATE-238 demonstrated a statistically significant improvement in RFS for patients randomized to the OPDIVO arm compared with the ipilimumab 10 mg/kg arm. Efficacy results are shown in Table 49 and Figure 5.
Table 49: Efficacy Results in CHECKMATE-238 | ||
| OPDIVO | Ipilimumab 10 mg/kg |
Recurrence-free Survival |
|
|
Number of events, n (%) | 154 (34%) | 206 (45%) |
Median (months) | NRa | NRa |
Hazard ratiob | 0.65 | |
Overall Survival |
|
|
Number of events, n (%)e | 100 (22%) | 111 (25%) |
Median (months) | NRa | NRa |
Hazard ratiob | 0.87 (0.67, 1.14) 0.3148 | |
a Not reached.
b Based on a stratified proportional hazards model.
c Based on a stratified log-rank test.
d p-value is compared with 0.0244 of the allocated alpha for this analysis.
e At the time of the final OS analysis, fewer overall survival events were observed than originally anticipated (approximately 302).
Figure 5: Recurrence-free Survival - CHECKMATE-238
Neoadjuvant treatment of NSCLC
Randomized, open-label, phase 3 study of nivolumab in combination with platinum-based chemotherapy vs. platinum-based chemotherapy (CA209816)
The safety and efficacy of nivolumab in combination with platinum-based chemotherapy for 3 cycles were evaluated in a phase 3, randomized, open-label study (CA209816). The study included patients with ECOG performance status 0 or 1, measurable disease (per RECIST version 1.1), and whose tumors were resectable, histologically confirmed Stage IB (≥ 4 cm), II, or IIIA NSCLC (per the 7th edition AJCC/Union for International Cancer Control (UICC) staging criteria).
The following selection criteria define patients with high risk of recurrence who are included in the therapeutic indication and are reflective of a patient population with stage II-IIIA disease according to the 7th edition AJCC/UICC staging criteria: any patient with a tumor size ≥5 cm; any patient with N1 or N2 disease (regardless of primary tumor size); patients with multiple tumor nodules in either the same lobe or different ipsilateral lobes; patients with tumors that are invasive of thoracic structures (directly invade visceral pleura, parietal pleura, chest wall, diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina); or tumors that involve the main bronchus; or tumors that are associated with atelectasis or obstructive pneumonitis that extends to the hilar region or involves the entire lung.
The study did not include patients who had N2 status with tumors also invading the mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, or with separate tumor nodule(s) in a different ipsilateral lobe.
Patients with unresectable or metastatic NSCLC, known EGFR mutations or ALK translocations (testing for EGFR mutations or ALK translocations was not mandatory at study entry), Grade 2 or greater peripheral neuropathy, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study. Randomization was stratified by tumor PD-L1 expression level (≥ 1% vs. < 1% or non-quantifiable), disease stage (IB/II vs. IIIA), and gender (male vs. female). Patients were enrolled regardless of their tumor PD-L1 status. Tumor PD-L1 expression was determined using the PD-L1 IHC 28-8 pharmDx assay.
A total of 358 patients were randomized to receive either nivolumab in combination with platinum-based chemotherapy (n = 179) or platinum-based chemotherapy (n = 179). Patients in the nivolumab in combination with chemotherapy arm received nivolumab 360 mg administered intravenously over 30 minutes in combination with platinum-based chemotherapy every 3 weeks for up to 3 cycles. Patients in the chemotherapy arm received platinum-based chemotherapy administered every 3 weeks for up to 3 cycles. Platinum-based chemotherapy consisted of investigator’s choice of paclitaxel 175 mg/m2 or 200 mg/m2 and carboplatin AUC 5 or AUC 6 (any histology); pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 (non-squamous histology); or gemcitabine 1000 mg/m2 or 1250 mg/m2 and cisplatin 75 mg/m2 (squamous histology). In the chemotherapy arm, two additional treatment regimen options included vinorelbine 25 mg/m2 or 30 mg/m2 and cisplatin 75 mg/m2; or docetaxel 60 mg/m2 or 75 mg/m2 and cisplatin 75 mg/m2 (any histology).
Tumor assessments were performed at baseline, within 14 days of surgery, every 12 weeks after surgery for 2 years, then every 6 months for 3 years, and every year for 5 years until disease recurrence or progression. The primary efficacy outcome measures were event-free survival (EFS) based on BICR assessment and pathological complete response rate (pCR) by blinded-independent pathology review (BIPR). OS was a key secondary efficacy outcome measure and exploratory endpoints included feasibility of surgery.
Baseline characteristics in the ITT population were generally balanced across treatment groups. The median age was 65 years (range: 34-84) with 51% of patients ≥ 65 years and 7% of patients ≥ 75 years; 50% of patients were Asian, 47% were white, and 71% were male. Baseline ECOG performance status was 0 (67%) or 1 (33%); 50% of patients with PD-L1 ≥ 1% and 43% with PD-L1 < 1%; 5% had Stage IB, 17% had Stage IIA, 13% had Stage IIB, and 64% had Stage IIIA disease; 51% had squamous and 49% had non-squamous histology; and 89% were former/current smokers. Definitive surgery was performed on 83% of the patients in the nivolumab in combination with chemotherapy arm and on 75% of the patients in the chemotherapy arm. Adjuvant systemic treatment was received by 14.8% of patients in the nivolumab in combination with chemotherapy arm and by 25% of patients in the chemotherapy arm.
At the final pCR analysis and pre-specified interim EFS analysis (minimum follow-up 21 months), in all randomized patients, a statistically significant improvement was demonstrated in pCR and EFS for patients randomized to nivolumab in combination with chemotherapy as compared to chemotherapy alone. The pCR response rate was 24% in the nivolumab in combination with chemotherapy arm and 2.2% in the chemotherapy arm (difference of pCR 21.6, 99% CI: 13.0, 30.3; odds ratio of pCR 13.9, 99% CI: 3.49, 55.75; stratified p-value < 0.0001). Median EFS was 31.6 months in the nivolumab in combination with chemotherapy arm and 20.8 months in the chemotherapy arm (HR = 0.63, 97.38% CI: 0.43, 0.91; stratified log-rank p-value 0.0052). The HR for OS was 0.57 (99.67% CI: 0.30, 1.07) for nivolumab in combination with chemotherapy vs. chemotherapy.
Exploratory subgroup analysis by tumor PD-L1 expression and disease stage
The key efficacy results for the subgroup of patients with tumor PD-L1 expression ≥ 1% and disease stage II-IIIA from an exploratory analysis with a minimum follow-up of 32.9 months are summarized in Table 50.
Table 50: Efficacy results in patients with tumor PD-L1 ≥1% and stage II-IIIA disease* (CA209816)
| nivolumab + chemotherapy | chemotherapy |
Event-free survival per BICR | ||
Events | 22 (27.2%) | 39 (45.3%) |
Hazard ratioa (95% CI) | 0.49 (0.29, 0.83) | |
Median (months)b (95% CI) | NR (44.42, NR) | 26.71 (13.40, NR) |
Pathologic complete response per BIPR | ||
Responses | 26 (32.1%) | 2 (2.3%) |
95% CIc | (22.2, 43.4) | (0.3, 8.1) |
Difference of pCR (95% CI)d | 29.8% (19.0, 40.7) | |
a Based on an unstratified Cox proportional hazards model.
b Kaplan-Meier estimate.
c Based on Clopper and Pearson method.
d Two-sided 95% confidence interval for unweighted difference was calculated using Newcombe method.
* 7th edition AJCC/UICC staging criteria.
Minimum follow-up for EFS was 32.9 months, data cut-off: 06-Sep-2022
pCR data cut-off: 28-Jul-2020
The Kaplan-Meier curves for EFS for the subgroup of patients with tumor PD-L1 expression ≥ 1% and stage II-IIIA disease, with a minimum follow-up of 32.9 months, are shown in Figure 6.
Figure 6: Kaplan-Meier curves of EFS in patients with tumor PD-L1 ≥ 1% and stage II‑IIIA disease (CA209816)
Number of Subjects at Risk
Nivolumab + chemotherapy | |||||||||||||||||||
| 81 | 69 | 62 | 59 | 58 | 55 | 53 | 51 | 51 | 50 | 47 | 37 | 32 | 21 | 10 | 5 | 1 | 1 | 0 |
Chemotherapy | |||||||||||||||||||
| 86 | 71 | 60 | 52 | 44 | 40 | 38 | 36 | 34 | 31 | 30 | 23 | 18 | 14 | 7 | 6 | 1 | 1 | 0 |
¾¦¾¾ | Nivolumab + chemotherapy (events: 22/81), median and 95% CI: NR (44.42, NR) |
‑ ‑ ‑r‑ ‑ ‑ | Chemotherapy (events: 39/86), median and 95% CI: 26.71 (13.40, NR) |
Based on data cut-off: 06‑Sep‑2022, minimum follow-up of 32.9 months
At the time of the updated EFS analysis, an interim analysis for OS was performed (minimum follow-up of 32.9 months). The exploratory, descriptive HR for OS in patients with tumor PD-L1 expression ≥ 1% and stage II-IIIA disease was 0.43 (95% CI: 0.22, 0.83) for nivolumab in combination with chemotherapy vs. chemotherapy. The Kaplan-Meier curves for OS for the subgroup of patients with tumor PD-L1 expression ≥ 1% and stage II-IIIA disease, with a minimum follow-up of 32.9 months, are shown in Figure 7.
Figure 7: Kaplan-Meier curves of OS in patients with tumour PD-L1 ≥ 1% and stage II‑IIIA disease (CA209816)
Number of Subjects at Risk
Nivolumab + chemotherapy | |||||||||||||||||||||
| 81 | 80 | 76 | 76 | 74 | 73 | 71 | 69 | 69 | 69 | 68 | 67 | 59 | 50 | 33 | 22 | 11 | 6 | 3 | 1 | 0 |
Chemotherapy | |||||||||||||||||||||
| 86 | 84 | 80 | 79 | 77 | 74 | 67 | 61 | 60 | 57 | 56 | 55 | 50 | 41 | 27 | 20 | 10 | 5 | 0 | 0 | 0 |
¾¦¾¾ | Nivolumab + chemotherapy (events: 13/81), median and 95% CI: NR |
‑ ‑ ‑r‑ ‑ ‑ | Chemotherapy (events: 29/86), median and 95% CI: NR |
Based on data cut-off: 06‑Sep‑2022, minimum follow-up of 32.9 months
Metastatic Non-Small Cell Lung Cancer
First-line Treatment of Metastatic or Recurrent NSCLC: In Combination with Ipilimumab and Platinum-Doublet Chemotherapy
CHECKMATE-9LA was a randomized, open-label trial in patients with metastatic or recurrent NSCLC. The trial included patients (18 years of age or older) with histologically confirmed Stage IV or recurrent NSCLC (per the 7th International Association for the Study of Lung Cancer classification [IASLC]), ECOG performance status 0 or 1, and no prior anticancer therapy (including EGFR and ALK inhibitors) for metastatic disease. Patients were enrolled regardless of their tumor PD-L1 status. Patients with known EGFR mutations or ALK translocations sensitive to available targeted inhibitor therapy, untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study. Patients with stable brain metastases were eligible for enrollment.
Patients were randomized 1:1 to receive either:
· OPDIVO 360 mg administered intravenously over 30 minutes every 3 weeks, ipilimumab 1 mg/kg administered intravenously over 30 minutes every 6 weeks, and platinum-doublet chemotherapy administered intravenously every 3 weeks for 2 cycles, or
· platinum-doublet chemotherapy administered every 3 weeks for 4 cycles.
Platinum-doublet chemotherapy consisted of either carboplatin (AUC 5 or 6) and pemetrexed 500 mg/m2, or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 for non-squamous NSCLC; or carboplatin (AUC 6) and paclitaxel 200 mg/m2 for squamous NSCLC. Patients with non-squamous NSCLC in the control arm could receive optional pemetrexed maintenance therapy. Stratification factors for randomization were tumor PD-L1 expression level (≥1% versus <1% or non-quantifiable), histology (squamous versus non-squamous), and sex (male versus female). Study treatment continued until disease progression, unacceptable toxicity, or for up to 2 years. Treatment could continue beyond disease progression if a patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients who discontinued combination therapy because of an adverse reaction attributed to ipilimumab were permitted to continue OPDIVO as a single agent as part of the study. Tumor assessments were performed every 6 weeks from the first dose of study treatment for the first 12 months, then every 12 weeks until disease progression or study treatment was discontinued. The primary efficacy outcome measure was OS. Additional efficacy outcome measures included PFS, ORR, and duration of response as assessed by BICR.
A total of 719 patients were randomized to receive either OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy (n=361) or platinum-doublet chemotherapy (n=358). The median age was 65 years (range: 26 to 86) with 51% of patients ³65 years and 10% of patients ³75 years. The majority of patients were White (89%) and male (70%). Baseline ECOG performance status was 0 (31%) or 1 (68%), 57% had tumors with PD-L1 expression ³1% and 37% had tumors with PD-L1 expression that was <1%, 32% had tumors with squamous histology and 68% had tumors with non-squamous histology, 17% had CNS metastases, and 86% were former or current smokers.
The study demonstrated a statistically significant benefit in OS, PFS, and ORR. Efficacy results from the prespecified interim analysis when 351 events were observed (87% of the planned number of events for final analysis) are presented in Table 51.
Table 51: Efficacy Results - CHECKMATE-9LA
| OPDIVO and Ipilimumab and Platinum-Doublet Chemotherapy (n=361) | Platinum-Doublet Chemotherapy (n=358) | ||
| Overall Survival | |||
| Events (%) | 156 (43.2) | 195 (54.5) | |
| Median (months) (95% CI) | 14.1 (13.2, 16.2) | 10.7 (9.5, 12.5) | |
| Hazard ratio (96.71% CI)a | 0.69 (0.55, 0.87) | ||
| Stratified log-rank p-valueb | 0.0006 | ||
| Progression-free Survival per BICR | |||
| Events (%) | 232 (64.3) | 249 (69.6) | |
| Hazard ratio (97.48% CI)a | 0.70 (0.57, 0.86) | ||
| Stratified log-rank p-valuec | 0.0001 | ||
| Median (months)d (95% CI) | 6.8 (5.6, 7.7) | 5.0 (4.3, 5.6) | |
| Overall Response Rate per BICR (%) | 38 | 25 | |
| (95% CI)e | (33, 43) | (21, 30) | |
| Stratified CMH test p-valuef | 0.0003 | ||
| Duration of Response per BICR | |||
| Median (months) (95% CI)d | 10.0 (8.2, 13.0) |
| |
a Based on a stratified Cox proportional hazard model.
b p-value is compared with the allocated alpha of 0.033 for this interim analysis.
c p-value is compared with the allocated alpha of 0.0252 for this interim analysis.
d Kaplan-Meier estimate.
e Confidence interval based on the Clopper and Pearson Method.
f p-value is compared with the allocated alpha of 0.025 for this interim analysis.
With an additional 4.6 months of follow-up, the hazard ratio for overall survival was 0.66 (95% CI: 0.55, 0.80) and median survival was 15.6 months (95% CI: 13.9, 20.0) and 10.9 months (95% CI: 9.5, 12.5) for patients receiving OPDIVO and ipilimumab and platinum-doublet chemotherapy or platinum-doublet chemotherapy, respectively (Figure 8).
Figure 8: Overall Survival - CHECKMATE-9LA
Second-line Treatment of Metastatic Squamous NSCLC
CHECKMATE-017 was a randomized (1:1), open-label trial in 272 patients with metastatic squamous NSCLC who had experienced disease progression during or after one prior platinum doublet-based chemotherapy regimen. Patients received OPDIVO 3 mg/kg by intravenous infusion every 2 weeks (n=135) or docetaxel 75 mg/m2 intravenously every 3 weeks (n=137). Randomization was stratified by prior paclitaxel vs. other prior treatment and region (US/Canada vs. Europe vs. Rest of World). This trial included patients regardless of their PD-L1 status. The trial excluded patients with autoimmune disease, medical conditions requiring systemic immunosuppression, symptomatic interstitial lung disease, or untreated brain metastasis. Patients with treated brain metastases were eligible if neurologically returned to baseline at least 2 weeks prior to enrollment, and either off corticosteroids, or on a stable or decreasing dose of <10 mg daily prednisone equivalents. The first tumor assessments were conducted 9 weeks after randomization and continued every 6 weeks thereafter. The major efficacy outcome measure was OS. Additional efficacy outcome measures were investigator-assessed ORR and PFS.
The trial population characteristics were: median age was 63 years (range: 39 to 85) with 44% ³65 years of age and 11% ³75 years of age. The majority of patients were White (93%) and male (76%); the majority of patients were enrolled in Europe (57%) with the remainder in US/Canada (32%) and the rest of the world (11%). Baseline ECOG performance status was 0 (24%) or 1 (76%) and 92% were former/current smokers. Baseline disease characteristics of the population as reported by investigators were Stage IIIb (19%), Stage IV (80%), and brain metastases (6%). All patients received prior therapy with a platinum-doublet regimen and 99% of patients had tumors of squamous-cell histology.
The trial demonstrated a statistically significant improvement in OS for patients randomized to OPDIVO as compared with docetaxel at the prespecified interim analysis when 199 events were observed (86% of the planned number of events for final analysis). Efficacy results are shown in Table 52 and Figure 9.
Table 52: Efficacy Results - CHECKMATE-017
| OPDIVO | Docetaxel | |
Overall Survival |
|
| |
Deaths (%) | 86 (64%) | 113 (82%) | |
Median (months) | 9.2 | 6.0 | |
Hazard ratio (95% CI)a | 0.59 (0.44, 0.79) | ||
p-valueb,c | 0.0002 | ||
Overall Response Rate | 27 (20%) | 12 (9%) | |
(95% CI) | (14, 28) | (5, 15) | |
p-valued | 0.0083 | ||
Complete response | 1 (0.7%) | 0 | |
Median duration of response (months) | NRe | 8.4 | |
Progression-free Survival |
|
| |
Disease progression or death (%) | 105 (78%) | 122 (89%) | |
Median (months) | 3.5 | 2.8 | |
Hazard ratio (95% CI)a | 0.62 (0.47, 0.81) | ||
p-valueb | 0.0004 | ||
a Based on a stratified proportional hazards model.
b Based on stratified log-rank test.
c p-value is compared with 0.0315 of the allocated alpha for this interim analysis.
d Based on the stratified Cochran-Mantel-Haenszel test.
e Not Reached
Figure 9: Overall Survival - CHECKMATE-017
Archival tumor specimens were retrospectively evaluated for PD-L1 expression. Across the trial population, 17% of 272 patients had non-quantifiable results. Among the 225 patients with quantifiable results, 47% had PD-L1 negative squamous NSCLC, defined as <1% of tumor cells expressing PD-L1 and 53% had PD-L1 positive squamous NSCLC, defined as ³1% of tumor cells expressing PD-L1. In pre-specified exploratory subgroup analyses, the hazard ratios for survival were 0.58 (95% CI: 0.37, 0.92) in the PD-L1 negative subgroup and 0.69 (95% CI: 0.45, 1.05) in the PD-L1 positive subgroup.
Second-line Treatment of Metastatic Non-Squamous NSCLC
CHECKMATE-057 was a randomized (1:1), open-label trial in 582 patients with metastatic non-squamous NSCLC who had experienced disease progression during or after one prior platinum doublet-based chemotherapy regimen. Appropriate prior targeted therapy in patients with known sensitizing EGFR mutation or ALK translocation was allowed. Patients received OPDIVO 3 mg/kg by intravenous infusion every 2 weeks (n=292) or docetaxel 75 mg/m2 intravenously every 3 weeks (n=290). Randomization was stratified by prior maintenance therapy (yes vs. no) and number of prior therapies (1 vs. 2). The trial excluded patients with autoimmune disease, medical conditions requiring systemic immunosuppression, symptomatic interstitial lung disease, or untreated brain metastasis. Patients with treated brain metastases were eligible if neurologically stable. The first tumor assessments were conducted 9 weeks after randomization and continued every 6 weeks thereafter. The major efficacy outcome measure was OS. Additional efficacy outcome measures were investigator-assessed ORR and PFS. In addition, prespecified analyses were conducted in subgroups defined by PD-L1 expression.
The trial population characteristics: median age was 62 years (range: 21 to 85) with 42% of patients ³65 years and 7% of patients ³75 years. The majority of patients were White (92%) and male (55%); the majority of patients were enrolled in Europe (46%) followed by the US/Canada (37%) and the rest of the world (17%). Baseline ECOG performance status was 0 (31%) or 1 (69%), 79% were former/current smokers, 3.6% had NSCLC with ALK rearrangement, 14% had NSCLC with EGFR mutation, and 12% had previously treated brain metastases. Prior therapy included platinum-doublet regimen (100%) and 40% received maintenance therapy as part of the first-line regimen. Histologic subtypes included adenocarcinoma (93%), large cell (2.4%), and bronchoalveolar (0.9%).
CHECKMATE-057 demonstrated a statistically significant improvement in OS for patients randomized to OPDIVO as compared with docetaxel at the prespecified interim analysis when 413 events were observed (93% of the planned number of events for final analysis). Efficacy results are shown in Table 53 and Figure 10.
Table 53: Efficacy Results CHECKMATE-057
| OPDIVO | Docetaxel |
Overall Survival |
|
|
Deaths (%) | 190 (65%) | 223 (77%) |
Median (months) | 12.2 | 9.4 |
Hazard ratio (95% CI)a | 0.73 (0.60, 0.89) | |
p-valueb,c | 0.0015 | |
Overall Response Rate | 56 (19%) | 36 (12%) |
(95% CI) | (15, 24) | (9, 17) |
p-valued | 0.02 | |
Complete response | 4 (1.4%) | 1 (0.3%) |
Median duration of response (months) | 17 | 6 |
Progression-free Survival |
|
|
Disease progression or death (%) | 234 (80%) | 245 (84%) |
Median (months) | 2.3 | 4.2 |
Hazard ratio (95% CI)a | 0.92 (0.77, 1.11) | |
p-valueb | 0.39 | |
a Based on a stratified proportional hazards model.
b Based on stratified log-rank test.
c p-value is compared with 0.0408 of the allocated alpha for this interim analysis.
d Based on the stratified Cochran-Mantel-Haenszel test.
e Not Reached
Figure 10: Overall Survival - CHECKMATE-057
Archival tumor specimens were evaluated for PD-L1 expression following completion of the trial. Across the trial population, 22% of 582 patients had non-quantifiable results. Of the remaining 455 patients, the proportion of patients in retrospectively determined subgroups based on PD-L1 testing using the PD-L1 IHC 28-8 pharmDx assay were: 46% PD-L1 negative, defined as <1% of tumor cells expressing PD-L1 and 54% had PD-L1 expression, defined as ³1% of tumor cells expressing PD-L1. Among the 246 patients with tumors expressing PD-L1, 26% had ³1% but <5% tumor cells with positive staining, 7% had ³5% but <10% tumor cells with positive staining, and 67% had ≥10% tumor cells with positive staining. Figures 11 and 12 summarize the results of prespecified analyses of OS and PFS in subgroups determined by percentage of tumor cells expressing PD-L1.
Figure 11: Forest Plot: OS Based on PD-L1 Expression - CHECKMATE-057
Figure 12: Forest Plot: PFS Based on PD-L1 Expression - CHECKMATE-057
Malignant Pleural Mesothelioma
CHECKMATE-743 was a randomized, open-label trial in patients with unresectable malignant pleural mesothelioma. The trial included patients with histologically confirmed and previously untreated malignant pleural mesothelioma with no palliative radiotherapy within 14 days of initiation of therapy. Patients with interstitial lung disease, active autoimmune disease, medical conditions requiring systemic immunosuppression, or active brain metastasis were excluded from the trial.
Patients were randomized 1:1 to receive either:
- OPDIVO 3 mg/kg over 30 minutes by intravenous infusion every 2 weeks and ipilimumab 1 mg/kg over 30 minutes by intravenous infusion every 6 weeks for up to 2 years, or
- cisplatin 75 mg/m2 and pemetrexed 500 mg/m2, or carboplatin 5 AUC and pemetrexed 500 mg/m2 administered every 3 weeks for 6 cycles.
Stratification factors for randomization were tumor histology (epithelioid vs. sarcomatoid or mixed histology subtypes) and sex (male vs. female). Study treatment continued for up to 2 years, or until disease progression or unacceptable toxicity. Patients who discontinued combination therapy because of an adverse reaction attributed to ipilimumab were permitted to continue OPDIVO as a single agent. Treatment could continue beyond disease progression if a patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Tumor assessments were performed every 6 weeks from the first dose of study treatment for the first 12 months, then every 12 weeks until disease progression or study treatment was discontinued. The primary efficacy outcome measure was OS. Additional efficacy outcome measures included PFS, ORR, and duration of response as assessed by BICR utilizing modified RECIST criteria.
A total of 605 patients were randomized to receive either OPDIVO in combination with ipilimumab (n=303) or chemotherapy (n=302). The median age was 69 years (range: 25 to 89), with 72% of patients ≥65 years and 26% ≥75 years; 85% were White, 11% were Asian, and 77% were male. Baseline ECOG performance status was 0 (40%) or 1 (60%), 35% had Stage III and 51% had Stage IV disease, 75% had epithelioid and 25% had non-epithelioid histology, 75% had tumors with PD-L1 expression ≥1%, and 22% had tumors with PD-L1 expression <1%.
The trial demonstrated a statistically significant improvement in OS for patients randomized to OPDIVO in combination with ipilimumab compared to chemotherapy. Efficacy results from the prespecified interim analysis are presented in Table 54 and Figure 13.
Table 54: Efficacy Results - CHECKMATE-743 | ||
| OPDIVO and Ipilimumab | Chemotherapy |
Overall Survivala | ||
Events (%) | 200 (66) | 219 (73) |
Median (months)b (95% CI) | 18.1 | 14.1 |
Hazard ratio (95% CI)c | 0.74 (0.61, 0.89) | |
Stratified log-rank p-valued | 0.002 | |
Progression-free Survival | ||
Events (%) | 218 (72) | 209 (69) |
Hazard ratio (95% CI)c | 1.0 (0.82, 1.21) | |
Median (months)b (95% CI) | 6.8 | 7.2 |
Overall Response Ratee | 40% | 43% |
(95% CI) | (34, 45) | (37, 49) |
Duration of Response | ||
Median (months)b | 11.0 | 6.7 |
a At the time of the interim analysis, 419 deaths (89% of the deaths needed for the final analysis) had occurred.
b Kaplan-Meier estimate.
c Stratified Cox proportional hazard model.
d p-value is compared with the allocated alpha of 0.0345 for this interim analysis.
e Based on confirmed response by BICR.
Figure 13: Overall Survival - CHECKMATE-743
In a prespecified exploratory analysis based on histology, in the subgroup of patients with epithelioid histology, the hazard ratio (HR) for OS was 0.85 (95% CI: 0.68, 1.06), with median OS of 18.7 months in the OPDIVO and ipilimumab arm and 16.2 months in the chemotherapy arm. In the subgroup of patients with non-epithelioid histology, the HR for OS was 0.46 (95% CI: 0.31, 0.70), with median OS of 16.9 months in the OPDIVO and ipilimumab arm and 8.8 months in the chemotherapy arm.
Advanced Renal Cell Carcinoma
First-line Renal Cell Carcinoma
CHECKMATE-214
CHECKMATE-214 was a randomized (1:1), open-label trial in patients with previously untreated advanced RCC. Patients were included regardless of their PD-L1 status. CHECKMATE-214 excluded patients with any history of or concurrent brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients were stratified by International Metastatic RCC Database Consortium (IMDC) prognostic score and region.
Efficacy was evaluated in intermediate/poor risk patients with at least 1 or more of 6 prognostic risk factors as per the IMDC criteria (less than one year from time of initial renal cell carcinoma diagnosis to randomization, Karnofsky performance status <80%, hemoglobin less than the lower limit of normal, corrected calcium of >10 mg/dL, platelet count greater than the upper limit of normal, and absolute neutrophil count greater than the upper limit of normal).
Patients were randomized to OPDIVO 3 mg/kg and ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses followed by OPDIVO 3 mg/kg intravenously every two weeks (n=425), or sunitinib 50 mg orally daily for the first 4 weeks of a 6-week cycle (n=422). Treatment continued until disease progression or unacceptable toxicity.
The trial population characteristics were: median age was 61 years (range: 21 to 85) with 38% ³65 years of age and 8% ³75 years of age. The majority of patients were male (73%) and White (87%) and 26% and 74% of patients had a baseline KPS of 70% to 80% and 90% to 100%, respectively.
The major efficacy outcome measures were OS, PFS (independent radiographic review committee [IRRC]-assessed) and confirmed ORR (IRRC-assessed) in intermediate/poor risk patients. In this population, the trial demonstrated statistically significant improvement in OS and ORR for patients randomized to OPDIVO and ipilimumab as compared with sunitinib (Table 55 and Figure 14). OS benefit was observed regardless of PD-L1 expression level. The trial did not demonstrate a statistically significant improvement in PFS. Efficacy results are shown in Table 55 and Figure 14.
Table 55: Efficacy Results - CHECKMATE-214 | ||
| Intermediate/Poor-Risk | |
| OPDIVO and Ipilimumab | Sunitinib |
Overall Survival |
|
|
Deaths (%) | 140 (32.9) | 188 (44.5) |
Median survival (months) | NRa | 25.9 |
Hazard ratio (99.8% CI)b | 0.63 (0.44, 0.89) | |
p-valuec,d | <0.0001 | |
Confirmed Overall Response Rate (95% CI) | 41.6% (36.9, 46.5) | 26.5% (22.4, 31.0) |
p-valuee,f | <0.0001 | |
Complete response (CR) | 40 (9.4) | 5 (1.2) |
Partial response (PR) | 137 (32.2) | 107 (25.4) |
Median duration of response (months) (95% CI) | NRa (21.8, NRa) | 18.2 (14.8, NRa) |
Progression-free Survival |
|
|
Disease progression or death (%) | 228 (53.6) | 228 (54.0) |
Median (months) | 11.6 | 8.4 |
Hazard ratio (99.1% CI)b | 0.82 (0.64, 1.05) | |
p-valuec | NSg | |
b Based on a stratified proportional hazards model.
c Based on a stratified log-rank test.
d p-value is compared to alpha 0.002 in order to achieve statistical significance.
e Based on the stratified DerSimonian-Laird test.
f p-value is compared to alpha 0.001 in order to achieve statistical significance.
g Not Significant at alpha level of 0.009.
Figure 14: Overall Survival (Intermediate/Poor Risk Population) - CHECKMATE-214
CHECKMATE-214 also randomized 249 favorable risk patients as per IMDC criteria to OPDIVO and ipilimumab (n=125) or to sunitinib (n=124). These patients were not evaluated as part of the efficacy analysis population. OS in favorable risk patients receiving OPDIVO and ipilimumab compared to sunitinib has a hazard ratio of 1.45 (95% CI: 0.75, 2.81). The efficacy of OPDIVO and ipilimumab in previously untreated renal cell carcinoma with favorable-risk disease has not been established.
CHECKMATE-9ER
CHECKMATE-9ER was a randomized, open-label study of OPDIVO combined with cabozantinib versus sunitinib in patients with previously untreated advanced RCC. CHECKMATE-9ER excluded patients with autoimmune disease or other medical conditions requiring systemic immunosuppression. Patients were stratified by IMDC prognostic score (favorable vs. intermediate vs. poor), PD-L1 tumor expression (≥1% vs. <1% or indeterminate), and region (US/Canada/Western Europe/Northern Europe vs. Rest of World).
Patients were randomized to OPDIVO 240 mg intravenously every 2 weeks and cabozantinib 40 mg orally daily (n=323), or sunitinib 50 mg orally daily for the first 4 weeks of a 6-week cycle (4 weeks on treatment followed by 2 weeks off) (n=328). Treatment continued until disease progression per RECIST v1.1 or unacceptable toxicity. Treatment beyond RECIST‑defined disease progression was permitted if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Tumor assessments were performed at baseline, after randomization at Week 12, then every 6 weeks until Week 60, and then every 12 weeks thereafter.
The trial population characteristics were: median age 61 years (range: 28 to 90) with 38% ³65 years of age and 10% ³75 years of age. The majority of patients were male (74%) and White (82%) and 23% and 77% of patients had a baseline KPS of 70% to 80% and 90% to 100%, respectively. Patient distribution by IMDC risk categories was 22% favorable, 58% intermediate, and 20% poor.
The major efficacy outcome measure was PFS (BICR assessed). Additional efficacy outcome measures were OS and ORR (BICR assessed). The trial demonstrated a statistically significant improvement in PFS, OS, and ORR for patients randomized to OPDIVO and cabozantinib compared with sunitinib. Consistent results for PFS were observed across pre-specified subgroups of IMDC risk categories and PD-L1 tumor expression status. An updated OS analysis was conducted when 271 deaths were observed based on the pre-specified number of deaths for the pre-planned final analysis of OS. Efficacy results are shown in Table 56 and Figures 15 and 16.
Table 56: Efficacy Results - CHECKMATE-9ER
Table 49: | ||
| OPDIVO and Cabozantinib | Sunitinib |
Progression-free Survival | ||
Disease progression or death (%) | 144 (45) | 191 (58) |
Median PFS (months)a (95% CI) | 16.6 (12.5, 24.9) | 8.3 (7.0, 9.7) |
Hazard ratio (95% CI)b | 0.51 (0.41, 0.64) | |
p-valuec,d | <0.0001 | |
Overall Survival | ||
Deaths (%) | 67 (21) | 99 (30) |
Median OS (months)a (95% CI) | NRe | NR (22.6, NRe) |
Hazard ratio (98.89% CI)b | 0.60 (0.40, 0.89) | |
p-valuec,d,f | 0.0010 | |
Updated Overall Survival |
|
|
Deaths (%) | 121 (37) | 150 (46) |
Median OS (months)a (95% CI) | 37.7 (35.5, NR) | 34.3 (29.0, NR) |
Hazard ratio (95% CI)b | 0.70 (0.55, 0.90) | |
Confirmed Objective Response Rate (95% CI)g | 55.7% (50.1, 61.2) | 27.1% (22.4, 32.3) |
p-valueh | <0.0001 | |
Complete Response | 26 (8%) | 15 (4.6%) |
Partial Response | 154 (48%) | 74 (23%) |
Median duration of response in months (95% CI)a | 20.2 (17.3, NRe) | 11.5 (8.3, 18.4) |
a Based on Kaplan-Meier estimates.
b Stratified Cox proportional hazards model.
c Based on stratified log-rank test
d 2-sided p-values from stratified log-rank test.
e Not Reached
f p-value is compared with the allocated alpha of 0.0111 for this interim analysis
g CI based on the Clopper-Pearson method.
h 2-sided p-value from Cochran-Mantel-Haenszel test.
Figure 15: Progression-free Survival - CHECKMATE-9ER
Figure 16: Updated overall Survival - CHECKMATE-9ER
In an exploratory analysis, the updated analysis of OS in patients with IMDC favorable, intermediate, intermediate/poor, and poor risk demonstrated a HR (95% CI) of 1.03 (0.55, 1.92), 0.74 (0.54, 1.01), 0.65 (0.50, 0.85), and 0.49 (0.31, 0.79), respectively.
Previously Treated Renal Cell Carcinoma
CHECKMATE-025
CHECKMATE-025 was a randomized (1:1), open-label trial in patients with advanced RCC who had experienced disease progression during or after one or two prior anti-angiogenic therapy regimens. Patients had to have a Karnofsky Performance Score (KPS) ≥70% and patients were included regardless of their PD-L1 status. The trial excluded patients with any history of or concurrent brain metastases, prior treatment with an mTOR inhibitor, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients were stratified by region, Memorial Sloan Kettering Cancer Center (MSKCC) Risk Group and the number of prior anti-angiogenic therapies.
Patients were randomized OPDIVO 3 mg/kg by intravenous infusion every 2 weeks (n=410) or everolimus 10 mg orally daily (n=411). The first tumor assessments were conducted 8 weeks after randomization and continued every 8 weeks thereafter for the first year and then every 12 weeks until progression or treatment discontinuation, whichever occurred later. The major efficacy outcome measure was overall survival (OS).
The trial population characteristics were: median age was 62 years (range: 18 to 88) with 40% ≥65 years of age and 9% ≥75 years of age. The majority of patients were male (75%) and White (88%) and 34% and 66% of patients had a baseline KPS of 70% to 80% and 90% to 100%, respectively. The majority of patients (77%) were treated with one prior anti-angiogenic therapy. Patient distribution by MSKCC risk groups was 34% favorable, 47% intermediate, and 19% poor.
The trial demonstrated a statistically significant improvement in OS for patients randomized to OPDIVO as compared with everolimus at the prespecified interim analysis when 398 events were observed (70% of the planned number of events for final analysis). OS benefit was observed regardless of PD-L1 expression level. Efficacy results are shown in Table 57 and Figure 17.
Table 57: Efficacy Results - CHECKMATE-025 | ||
| OPDIVO | Everolimus |
Overall Survival |
|
|
Deaths (%) | 183 (45) | 215 (52) |
Median survival (months) (95% CI) | 25.0 (21.7, NRa) | 19.6 (17.6, 23.1) |
Hazard ratio (95% CI)b | 0.73 (0.60, 0.89) | |
p-valuec,d | 0.0018 | |
Confirmed Overall Response Rate (95% CI) | 21.5% (17.6, 25.8) | 3.9% (2.2, 6.2) |
Median duration of response (months) (95% CI) | 23.0 (12.0, NRa) | 13.7 (8.3, 21.9) |
Median time to onset of confirmed response (months) (min, max) | 3.0 (1.4, 13.0) | 3.7 (1.5, 11.2) |
a Not Reached.
b Based on a stratified proportional hazards model.
c Based on a stratified log-rank test.
d p-value is compared with 0.0148 of the allocated alpha for this interim analysis.
Figure 15: Overall Survival - CHECKMATE-025
Classical Hodgkin Lymphoma
Two studies evaluated the efficacy of OPDIVO as a single agent in adult patients with cHL after failure of autologous HSCT.
CHECKMATE-205 was a single-arm, open-label, multicenter, multicohort trial in cHL. CHECKMATE-039 was an open-label, multicenter, dose escalation trial that included cHL. Both studies included patients regardless of their tumor PD-L1 status and excluded patients with ECOG performance status of 2 or greater, autoimmune disease, symptomatic interstitial lung disease, hepatic transaminases more than 3 times ULN, creatinine clearance <40 mL/min, prior allogeneic HSCT, or chest irradiation within 24 weeks. In addition, both studies required an adjusted diffusion capacity of the lungs for carbon monoxide (DLCO) of over 60% in patients with prior pulmonary toxicity.
Patients received OPDIVO 3 mg/kg by intravenous infusion every 2 weeks until disease progression, maximal clinical benefit, or unacceptable toxicity. A cycle consisted of one dose. Dose reduction was not permitted.
Efficacy was evaluated by ORR as determined by an IRRC. Additional outcome measures included duration of response (DOR).
Efficacy was evaluated in 95 patients in CHECKMATE-205 and CHECKMATE-039 combined who had failure of autologous HSCT and post-transplantation brentuximab vedotin. The median age was 37 years (range: 18 to 72). The majority were male (64%) and White (87%). Patients had received a median of 5 prior systemic regimens (range: 2 to 15). They received a median of 27 doses of OPDIVO (range: 3 to 48), with a median duration of therapy of 14 months (range: 1 to 23 months). Efficacy results are shown in Table 58.
Table 58: Efficacy in cHL after Autologous HSCT and Post-transplantation Brentuximab Vedotin
CHECKMATE-205 and CHECKMATE-039 (n=95) | |
Overall Response Rate, n (%)a (95% CI) | 63 (66%) (56, 76) |
Complete remission rate (95% CI) | 6 (6%) (2, 13) |
Partial remission rate (95% CI) | 57 (60%) (49, 70) |
Duration of Response (months) Medianb (95% CI) Rangec | 13.1 (9.5, NRd) 0+, 23.1+ |
Time to Response (months) Median Range | 2.0 0.7, 11.1 |
a Per 2007 revised International Working Group criteria.
b Kaplan-Meier estimate. Among responders, the median follow-up for DOR, measured from the date of first response, was 9.9 months.
c A + sign indicates a censored value.
d Not Reached
Efficacy was also evaluated in 258 patients in CHECKMATE-205 and CHECKMATE-039 combined who had relapsed or progressive cHL after autologous HSCT. The analysis included the group described above. The median age was 34 years (range: 18 to 72). The majority were male (59%) and White (86%). Patients had a median of 4 prior systemic regimens (range: 2 to 15), with 85% having 3 or more prior systemic regimens and 76% having prior brentuximab vedotin. Of the 195 patients having prior brentuximab vedotin, 17% received it only before autologous HSCT, 78% received it only after HSCT, and 5% received it both before and after HSCT. Patients received a median of 21 doses of OPDIVO (range: 1 to 48), with a median duration of therapy of 10 months (range: 0 to 23 months). Efficacy results are shown in Table 59.
Table 59: Efficacy in cHL after Autologous HSCT
CHECKMATE-205 and CHECKMATE-039 (n=258) | |
Overall Response Rate, n (%) (95% CI) | 179 (69%) (63, 75) |
Complete remission rate (95% CI) | 37 (14%) (10, 19) |
Partial remission rate (95% CI) | 142 (55%) (49, 61) |
Duration of Response (months) Mediana,b (95% CI) Range | NRc (12.0, NRc) 0+, 23.1+ |
Time to Response (months) Median Range | 2.0 0.7, 11.1 |
a Kaplan-Meier estimate. Among responders, the median follow-up for DOR, measured from the date of first response, was 6.7 months.
b The estimated median duration of PR was 13.1 months (95% CI, 9.5, NE). The median duration of CR was not reached.
c Not Reached
Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck
CHECKMATE-141 was a randomized (2:1), active-controlled, open-label trial enrolling patients with metastatic or recurrent SCCHN who had experienced disease progression during or within 6 months of receiving platinum-based therapy administered in either the adjuvant, neo-adjuvant, primary (unresectable locally advanced) or metastatic setting. The trial excluded patients with autoimmune disease, medical conditions requiring immunosuppression, recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary histology, salivary gland or non-squamous histologies (e.g., mucosal melanoma), or untreated brain metastasis. Patients with treated brain metastases were eligible if neurologically stable. Patients were randomized to receive OPDIVO 3 mg/kg by intravenous infusion every 2 weeks or investigator’s choice of cetuximab (400 mg/m2 initial dose intravenously followed by 250 mg/m2 weekly), or methotrexate (40 to 60 mg/m2 intravenously weekly), or docetaxel (30 to 40 mg/m2 intravenously weekly).
Randomization was stratified by prior cetuximab treatment (yes/no). The first tumor assessments were conducted 9 weeks after randomization and continued every 6 weeks thereafter. The major efficacy outcome measure was OS. Additional efficacy outcome measures were PFS and ORR.
A total of 361 patients were randomized; 240 patients to the OPDIVO arm and 121 patients to the investigator’s choice arm (docetaxel: 45%; methotrexate: 43%; and cetuximab: 12%). The trial population characteristics were: median age was 60 years (range: 28 to 83) with 31% ³65 years of age, 83% were White, 12% Asian, and 4% were Black, and 83% male. Baseline ECOG performance status was 0 (20%) or 1 (78%), 76% were former/current smokers, 90% had Stage IV disease, 45% of patients received only one prior line of systemic therapy, the remaining 55% received two or more prior lines of systemic therapy, and 25% had HPV p16-positive tumors, 24% had HPV p16-negative tumors, and 51% had unknown status.
The trial demonstrated a statistically significant improvement in OS for patients randomized to OPDIVO as compared with investigator’s choice at a pre-specified interim analysis (78% of the planned number of events for final analysis). There were no statistically significant differences between the two arms for PFS (HR=0.89; 95% CI: 0.70, 1.13) or ORR (13.3% [95% CI: 9.3, 18.3] vs. 5.8% [95% CI: 2.4, 11.6] for nivolumab and investigator’s choice, respectively). Efficacy results are shown in Table 60 and Figure 18.
Table 60: Overall Survival CHECKMATE-141
| OPDIVO | Cetuximab, Methotrexate or Docetaxel |
Overall Survival |
|
|
Deaths (%) | 133 (55%) | 85 (70%) |
Median (months) | 7.5 (5.5, 9.1) | 5.1 (4.0, 6.0) |
Hazard ratio (95% CI)a | 0.70 (0.53, 0.92) | |
p-valueb,c | 0.0101
| |
a Based on stratified proportional hazards model.
b Based on stratified log-rank test.
c p-value is compared with 0.0227 of the allocated alpha for this interim analysis.
Figure 18: Overall Survival - CHECKMATE-141
Archival tumor specimens were retrospectively evaluated for PD-L1 expression using the PD-L1 IHC 28-8 pharmDx assay. Across the trial population, 28% (101/361) of patients had non-quantifiable results. Among the 260 patients with quantifiable results, 43% (111/260) had PD-L1 negative SCCHN, defined as <1% of tumor cells expressing PD-L1, and 57% (149/260) had PD-L1 positive SCCHN, defined as ³1% of tumor cells expressing PD-L1. In pre-specified exploratory subgroup analyses, the hazard ratio for survival was 0.89 (95% CI: 0.54, 1.45) with median survivals of 5.7 and 5.8 months for the nivolumab and chemotherapy arms, respectively, in the PD-L1 negative subgroup. The HR for survival was 0.55 (95% CI: 0.36, 0.83) with median survivals of 8.7 and 4.6 months for the nivolumab and chemotherapy arms, respectively, in the PD-L1 positive SCCHN subgroup.
Urothelial Carcinoma
Adjuvant Treatment of UC at High Risk of Recurrence
CHECKMATE-274 was a randomized, double-blind, placebo‑controlled study of adjuvant OPDIVO in patients who were within 120 days of radical resection (R0) of UC of the bladder or upper urinary tract (renal pelvis or ureter) at high risk of recurrence. High risk of recurrence was defined as either 1) ypT2-ypT4a or ypN+ for patients who received neoadjuvant cisplatin or 2) pT3-pT4a or pN+ for patients who did not receive neoadjuvant cisplatin and who also either were ineligible for or refused adjuvant cisplatin. Patients were randomized 1:1 to receive OPDIVO 240 mg or placebo by intravenous infusion every 2 weeks until recurrence or until unacceptable toxicity for a maximum treatment duration of 1 year. Patients were stratified by pathologic nodal status (N+ vs. N0/x with <10 nodes removed vs. N0 with ³10 nodes removed), tumor cells expressing PD-L1 (³1% vs. <1%/indeterminate as determined by the central lab using the PD‑L1 IHC 28-8 pharmDx assay) and use of neoadjuvant cisplatin (yes vs. no).
The trial population characteristics were: median age of 67 years (range: 30 to 92); 76% male; 76% White, 22% Asian, 0.7% Black, and 0.1% American Indian or Alaska Native. Of the 335 (47%) of patients with node-positive UC, 44 (6%) had non-muscle-invasive (<pT2) primary tumors. ECOG performance status was 0 (63%), 1 (35%), or 2 (2%). Prior neoadjuvant cisplatin had been given to 43% of patients; of the 57% who did not receive prior neoadjuvant cisplatin, reasons listed were ineligibility (22%), patient preference (33%), and other/not reported (2%). Tumor PD-L1 expression was ≥1% in 40% of patients, and 21% of patients had upper tract UC.
The major efficacy outcome measures were investigator-assessed DFS in all randomized patients and in patients with tumors expressing PD-L1 ≥1%. DFS was defined as time to first recurrence (local urothelial tract, local non-urothelial tract, or distant metastasis), or death. Additional efficacy outcome measures included OS.
At the pre-specified interim analysis, CHECKMATE-274 demonstrated a statistically significant improvement in DFS for patients randomized to OPDIVO vs. placebo in the all randomized patient population, as well as in the subpopulation of patients with PD-L1 ≥1%, as shown in Table 61 and Figure 19.
In exploratory subgroup analyses in patients with upper tract UC (n=149), no improvement in DFS was observed in the nivolumab arm compared to the placebo arm. The unstratified DFS hazard ratio estimate was 1.15 (95% CI: 0.74, 1.80).
In an exploratory subgroup analysis in patients with PD-L1 expression of <1% (n=414), the unstratified DFS hazard ratio estimate was 0.83 (95% CI: 0.64, 1.08).
OS data is immature with 33% of deaths in the overall randomized population. In the UTUC subpopulation, 37 deaths occurred (20 in the nivolumab arm, 17 in the placebo arm).
Table 61: Efficacy Results - CHECKMATE-274
| All Randomized | PD-L1 ³1% | |||
OPDIVO (n=353) | Placebo (n=356) | OPDIVO (n=140) | Placebo (n=142) | |
| Disease-free Survival | ||||
Eventsa, n (%) Local recurrence Distant recurrence Death | 170 (48) 47 (13) 108 (31) 14 (4) | 204 (57) 64 (18) 127 (36) 10 (3) | 55 (39) 10 (7) 40 (29) 5(4) | 81 (57) 24 (17) 52 (37) 5 (4) |
Median DFS (months)b (95% CI) | 20.8 (16.5, 27.6) | 10.8 (8.3, 13.9) | N.R. (21.2, N.E.) | 8.4 (5.6, 21.2) |
Hazard ratioc (95% CI) | 0.70 (0.57, 0.86) | 0.55 (0.39, 0.77) | ||
| p-value | 0.0008d | 0.0005e | ||
N.R. Not reached, N.E. Not estimable
a Includes disease at baseline events (protocol deviations): n=1 in OPDIVO arm and n=3 in placebo arm.
b Based on Kaplan-Meier estimates.
c Stratified Cox proportional hazard model. Hazard ratio is OPDIVO over placebo.
d Log-rank test stratified by prior neoadjuvant cisplatin, pathological nodal status, PD-L1 status (≥1% vs <1%/indeterminate). Boundary for statistical significance in all randomized patients: p‑value <0.01784.
e Log-rank test stratified by prior neoadjuvant cisplatin, pathological nodal status. Boundary for statistical significance in all randomized patients with PD-L1 ³1%: p-value <0.01282.
Figure 19: Disease-free Survival in All Randomized Patients - CHECKMATE-274
First-line Treatment of Unresectable or Metastatic UC
CHECKMATE-901 was a randomized, open-label study in patients with previously untreated unresectable or metastatic UC. Prior neoadjuvant or adjuvant chemotherapy were permitted as long as the disease recurrence took place ≥12 months from completion of therapy. Patients who were ineligible for cisplatin and those with active CNS metastases were excluded. Stratification factors for randomization were PD-L1 status (≥1% vs. <1% or indeterminate) and liver metastasis. Patients were randomized 1:1 to receive either:
· OPDIVO 360 mg and cisplatin 70 mg/m2 on Day 1 and gemcitabine 1000 mg/m2 on Days 1 and 8 of a 21-day cycle of a 21-day cycle for up to 6 cycles followed by single-agent OPDIVO 480 mg every 4 weeks until disease progression or unacceptable toxicity. In the absence of disease progression or unacceptable toxicity, OPDIVO was continued for up to 2 years from first dose.
· Cisplatin 70 mg/m2 on Day 1 and gemcitabine 1000 mg/m2 on Days 1 and 8 of a 21-day cycle for up to 6 cycles, until disease progression or unacceptable toxicity.
The major efficacy outcome measures were OS and PFS as assessed by BICR using RECIST v1.1. Additional efficacy outcome measures included ORR as assessed by BICR.
The median age was 65 years of age (range: 32 to 86) with 51% of patients ≥65 years of age and 12% of patients ≥75 years of age, 23% were Asian, 72% were White, 0.3% were Black, 0.3% were American Indian or Alaska Native, 4.9% were Other, 12% were Hispanic or Latino, and 77% were male. Baseline ECOG performance status was 0 (53%) or 1 (46%). At baseline, 87% of patients had metastatic UC, including 20% with liver metastases, 11% had locally advanced UC, and 51% had UC histologic variants. Forty-nine (16%) in the OPDIVO in combination with cisplatin-based chemotherapy arm and 43 (14%) in the cisplatin-based chemotherapy arm switched from cisplatin to carboplatin after at least one cycle of cisplatin.
Efficacy results are presented in Table 62 and Figures 20 and 21.
Table 62: Efficacy Results – CHECKMATE 901 | ||
| OPDIVO and Cisplatin and Gemcitabine | Cisplatin and Gemcitabine (n=304) |
Overall Survival (OS) |
|
|
Events, n (%) | 172 (56.6) | 193 (63.5) |
Median (months) (95% CI)a | 21.7 | 18.9 |
Hazard ratio (95% CI)b | 0.78 | |
p-valuec | 0.0171 | |
Progression-free Survival (PFS)d |
|
|
Events, n (%) | 211 (69.4) | 191 (62.8) |
Median (months) (95% CI)a | 7.9 | 7.6 |
Hazard ratio (95% CI)b | 0.72 | |
p-valuec | 0.0012 | |
Objective Response Rate (ORR)d |
| |
Response rate, n (%) (95% CI) | 175 (57.6%) (51.8, 63.2) | 131 (43.1%) (37.5, 48.9) |
Complete response rate, n (%) | 66 (22%) | 36 (12%) |
Partial response rate, n (%) | 109 (36%) | 95 (31%) |
Duration of Response (DoR) |
| |
Median (months) (95% CI)a | 9.5 | 7.3 |
a Based on Kaplan-Meier Estimates
b Stratified Cox proportional hazard model.
c 2 sided p values from stratified log-rank test.
d Assessed by BICR.
Figure 20: Overall Survival - CHECKMATE-901
Figure 21: Progression-free Survival - CHECKMATE-901
Previously Treated Advanced or Metastatic UC
CHECKMATE-275 was a single-arm trial in 270 patients with locally advanced or metastatic UC who had disease progression during or following platinum-containing chemotherapy or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen. Patients were excluded for active brain or leptomeningeal metastases, active autoimmune disease, medical conditions requiring systemic immunosuppression, and ECOG performance status >1. Patients received OPDIVO 3 mg/kg by intravenous infusion every 2 weeks until unacceptable toxicity or either radiographic or clinical progression. Tumor response assessments were conducted every 8 weeks for the first 48 weeks and every 12 weeks thereafter. Major efficacy outcome measures included confirmed ORR as assessed by IRRC using RECIST v1.1 and DOR.
The median age was 66 years (range: 38 to 90), 78% were male, 86% were White. Twenty-seven percent had non-bladder urothelial carcinoma and 84% had visceral metastases. Thirty-four percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant therapy. Twenty-nine percent of patients had received ≥2 prior systemic regimens in the metastatic setting. Thirty-six percent of patients received prior cisplatin only, 23% received prior carboplatin only, and 7% were treated with both cisplatin and carboplatin in the metastatic setting. Forty-six percent of patients had an ECOG performance status of 1. Eighteen percent of patients had a hemoglobin <10 g/dL, and twenty-eight percent of patients had liver metastases at baseline. Patients were included regardless of their PD-L1 status.
Tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory and the results were used to define subgroups for pre-specified analyses. Of the 270 patients, 46% were defined as having PD-L1 expression of ≥1% (defined as ≥1% of tumor cells expressing PD-L1). The remaining 54% of patients were classified as having PD-L1 expression of <1% (defined as <1% of tumor cells expressing PD-L1). Confirmed ORR in all patients and the two PD-L1 subgroups are shown in Table 63. Median time to response was 1.9 months (range: 1.6 - 7.2). In 77 patients who received prior systemic therapy only in the neoadjuvant or adjuvant setting, the ORR was 23.4% (95% CI: 14.5%, 34.4%).
Table 63: Efficacy Results CHECKMATE-275
All Patients N=270 | PD-L1 <1% N=146 | PD-L1 ≥1% N=124 | |
Confirmed Overall Response Rate, n (%) (95% CI) | 53 (19.6%) (15.1, 24.9) | 22 (15.1%) (9.7, 21.9) | 31 (25.0%) (17.7, 33.6) |
| Complete response rate | 7 (2.6%) | 1 (0.7%) | 6 (4.8%) |
| Partial response rate | 46 (17.0%) | 21 (14.4%) | 25 (20.2%) |
Median Duration of Responsea (months) (range) | 10.3 (1.9+, 12.0+) | 7.6 (3.7, 12.0+) | NRb (1.9+, 12.0+) |
a Estimated from the Kaplan-Meier Curve.
b Not Reached
Esophageal Cancer
Esophageal Cancer
Adjuvant Treatment of Resected Esophageal or Gastroesophageal Junction Cancer
CHECKMATE-577 was a randomized, multicenter, double-blind trial in 794 patients with completely resected (negative margins) esophageal or gastroesophageal junction cancer who had residual pathologic disease following concurrent chemoradiotherapy (CRT). Patients were randomized (2:1) to receive either OPDIVO 240 mg or placebo by intravenous infusion over 30 minutes every 2 weeks for 16 weeks followed by 480 mg or placebo by intravenous infusion over 30 minutes every 4 weeks beginning at week 17. Treatment was until disease recurrence, unacceptable toxicity, or for up to 1 year in total duration. Enrollment required complete resection within 4 to 16 weeks prior to randomization. The trial excluded patients who did not receive CRT prior to surgery, had stage IV resectable disease, autoimmune disease, or any condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive medications. Randomization was stratified by tumor PD-L1 status (≥1% vs. <1% or indeterminate or non-evaluable), pathologic lymph node status (positive ≥ypN1 vs. negative ypN0), and histology (squamous vs. adenocarcinoma). The major efficacy outcome measure was disease-free survival (DFS) defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant from the primary resected site) or death, from any cause, whichever occurred first as assessed by the investigator prior to subsequent anti-cancer therapy. Patients on treatment underwent imaging for tumor recurrence every 12 weeks for 2 years, and a minimum of one scan every 6 to 12 months for years 3 to 5.
The trial population characteristics were: median age 62 years (range: 26 to 86), 36% were ³65 years of age, 85% were male, 15% were Asian, 82% were White, and 1.1% were Black. Disease characteristics were AJCC Stage II (35%) or Stage III (65%) at initial diagnosis carcinoma, EC (60%) or GEJC (40%) at initial diagnosis, with pathologic positive lymph node status (58%) at study entry and histological confirmation of predominant adenocarcinoma (71%) or squamous cell carcinoma (29%). The baseline Tumor PD-L1 status ≥1% was positive for 16% of patients and negative for 72% of patients. Baseline ECOG performance status was 0 (58%) or 1 (42%).
CHECKMATE-577 demonstrated a statistically significant improvement in DFS for patients randomized to the OPDIVO arm as compared with the placebo arm. DFS benefit was observed regardless of tumor PD-L1 expression and histology.
Efficacy results are shown in Table 64 and Figure 22.
Table 64: Efficacy Results - CHECKMATE-577
| OPDIVO | Placebo |
Disease-free Survival |
|
|
Number of events, n (%) | 241 (45%) | 155 (59%) |
Median (months) | 22.4 (16.6, 34.0) | 11.0 (8.3, 14.3) |
Hazard ratioa (95% CI) | 0.69 (0.56, 0.85) | |
p-valueb | 0.0003 | |
a Based on a stratified proportional hazards model.
b Based on a stratified log-rank test.
Figure 22: Disease-free Survival - CHECKMATE-577
First-line Treatment of Unresectable Advanced or Metastatic ESCC
CHECKMATE-648 was a randomized, active-controlled, open-label trial in patients with previously untreated unresectable advanced, recurrent or metastatic ESCC (squamous or adenosquamous histology). The trial enrolled patients whose tumor was evaluable for tumor cell (TC) PD-L1 expression [also called PD-L1 tumor proportion score (TPS)], which was evaluated using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory. A retrospective scoring of a patient’s tumor PD-L1 status using Combined Positive Score (CPS), was also conducted using the PD-L1-stained tumor specimens used for randomization. Patients were not amenable to chemoradiation or surgery with curative intent. Prior treatment with curative intent was allowed if completed more than six months prior to trial enrollment. The trial excluded patients with brain metastasis that were symptomatic, had active autoimmune disease, used systemic corticosteroids or immunosuppressants, or patients at high risk of bleeding or fistula due to apparent invasion of tumor to organs adjacent to the esophageal tumor. Patients were randomized to receive one of the following treatments:
· OPDIVO 240 mg on days 1 and 15, fluorouracil 800 mg/m2/day intravenously on days 1 through 5 (for 5 days), and cisplatin 80 mg/m2 intravenously on day 1 (of a 4-week cycle).
· OPDIVO 3 mg/kg every 2 weeks in combination with ipilimumab 1 mg/kg every 6 weeks.
· Fluorouracil 800 mg/m2/day intravenously on days 1 through 5 (for 5 days), and cisplatin 80 mg/m2 intravenously on day 1 (of a 4-week cycle).
Patients received OPDIVO until disease progression, unacceptable toxicity, or up to 2 years. In patients who received OPDIVO in combination with chemotherapy and in whom either fluorouracil and/or cisplatin were discontinued, other components of the treatment regimen were allowed to be continued. Patients who discontinued combination therapy because of an adverse reaction attributed to ipilimumab were permitted to continue OPDIVO as a single agent.
Randomization was stratified by TC PD-L1 expression (≥1% vs. <1% or indeterminate), region (East Asia vs. Rest of Asia vs. Rest of World), ECOG performance status (0 vs. 1), and number of organs with metastases (≤1 vs. ≥2). The major efficacy outcome measures were OS and BICR-assessed PFS in patients with TC PD-L1 expression ≥ 1%. Additional efficacy measures included OS in all randomized patients, BICR-assessed PFS in all randomized patients, and ORR assessed by BICR in TC PD-L1 expression ≥ 1% and in all randomized patients. The tumor assessments per RECIST v1.1 were conducted every 6 weeks up to and including week 48, then every 12 weeks thereafter.
A total of 970 patients were randomized in CHECKMATE-648 study among whom 965 and 906 patients had quantifiable TC PD-L1 expression and CPS at baseline, respectively. The trial population characteristics for all randomized patients were median age 64 years (range: 26 to 90), 47% were ³65 years of age, 82% were male, 71% were Asian, 26% were White, and 1.1% were Black. Patients had histological confirmation of squamous cell carcinoma (98%) or adenosquamous cell carcinoma (1.9%) in the esophagus. Baseline ECOG performance status was 0 (47.0%) or 1 (53%).
Efficacy results are shown in Table 65 and Figures 23 and 24.
Table 65: Efficacy Results - CHECKMATE-648
| OPDIVO with Cisplatin and Fluorouracil | OPDIVO and Ipilimumab | Cisplatin and Fluorouracil | OPDIVO with Cisplatin and Fluorouracil | OPDIVO and Ipilimumab | Cisplatin and Fluorouracil |
| All Patients | TC PD-L1 expression ≥ 1% | ||||
Overall Survival | ||||||
Deaths (%) | 209 (65) | 216 (66) | 232 (72) | 98 (62) | 106 (67) | 121 (77) |
Median (months) (95% CI) | 13.2 (11.1, 15.7) | 12.8 (11.3, 15.5) | 10.7 (9.4, 11.9) | 15.4 (11.9, 19.5) | 13.7 (11.2, 17.0) | 9.1 (7.7, 10) |
Hazard ratio (95% CI)b | 0.74 (0.61, 0.90) | 0.78 (0.65, 0.95) | - | 0.54 (0.41, 0.71) | 0.64 (0.49, 0.84) | - |
p-valuec | 0.0021S1 | 0.0110 S2 | - | < 0.0001S3 | 0.0010S4 | - |
Progression-free Survivala | ||||||
Disease progression or death (%) | 235 (73) | 258 (79) | 210 (65) | 117 (74) | 123 (78) | 100 (64) |
Median (months) (95% CI) | 5.8 (5.6, 7.0) | 2.9 (2.7, 4.2) | 5.6 (4.3, 5.9) | 6.9 (5.7, 8.3) | 4.0 (2.4, 4.9) | 4.4 (2.9, 5.8) |
Hazard ratio (95% CI)b | 0.81 (0.67, 0.99) | 1.26 (1.04, 1.52) | - | 0.65 (0.49, 0.86) | 1.02 (0.78, 1.34) | - |
p-valuec | NS | NT | - | 0.0023S5 | NS | - |
Overall Response Rate, n (%)a, NT | 152 (47.4) | 90 (27.7) | 87 (26.9) | 84 (53.2) | 56 (35.4) | 31 (19.7) |
(95% CI) | (41.8, 53.0) | (22.9, 32.9) | (22.1, 32.0) | (45.1, 61.1) | (28.0, 43.4) | (13.8, 26.8) |
Complete response (%) | 43 (13.4) | 36 (11.1) | 20 (6.2) | 26 (16.5) | 28 (17.7) | 8 (5.1) |
Partial response (%) | 109 (34.0) | 54 (16.6) | 67 (20.7) | 58 (36.7) | 28 (17.7) | 23 (14.6) |
Duration of Response (months)a | ||||||
Median (95% CI) | 8.2 (6.9, 9.7) | 11.1 (8.3, 14.0) | 7.1 (5.7, 8.2) | 8.4 (6.9, 12.4) | 11.8 (7.1, 27.4) | 5.7 (4.4, 8.7) |
Range | 1.4+, 35.9+ | 1.4+, 34.5+ | 1.4+, 31.8+ | 1.4+, 34.6 | 1.4+, 34.5+ | 1.4+, 31.8+ |
a Assessed by BICR.
b Based on stratified Cox proportional hazard model. Hazard ratios are reported for each OPDIVO containing arm compared to chemotherapy within each analysis population.
c Based on a stratified 2-sided log-rank test.
S1, S2, S3, S4, S5 Significant p-value compared to stopping boundary of 0.009, 0.018, 0.005, 0.014, and 0.015 respectively.
NS: Not Statistically significant, NT: Not evaluated for statistical significance as per pre-specified hierarchical testing procedure
Figure 23: Overall Survival – CHECKMATE-648
(A) OS in All Randomized Patients
(B) OS in TC PD-L1 ≥1%
Figure 24: Progression Survival – CHECKMATE-648
(A) PFS in All Randomized Patients
(B) PFS in TC PD-L1 ≥1%
Exploratory subgroup analyses of patients with TC PD-L1 expression <1% (n=492) were conducted. OS results for each OPDIVO containing arm compared to chemotherapy were:
· OPDIVO with Chemotherapy (n=163) vs. Chemotherapy (n=165): unstratified OS HR was 0.99 (95% CI: 0.76, 1.29) with median OS of 12 months (95% CI: 9.9, 15.5) on the OPDIVO with Chemotherapy arm and 12.2 months (95% CI: 10.7, 14) on the Chemotherapy arm
· OPDIVO with Ipilimumab (n=164) vs. Chemotherapy (n=165): unstratified OS HR was 0.97 (95% CI: 0.74, 1.26) with median OS of 12 months (95% CI: 10.1, 16.0) on the OPDIVO with Ipilimumab arm and 12.2 months (95% CI: 10.7, 14) on the Chemotherapy arm
Exploratory subgroup analyses were also conducted by PD-L1 status per CPS (≥1 and <1) for each OPDIVO containing arm compared to chemotherapy. Among the 906 patients with quantifiable PD-L1 CPS at baseline, 278 in the OPDIVO with chemotherapy arm, 266 in the OPDIVO with Ipilimumab arm, and 280 in the chemotherapy arm had PD-L1 CPS≥1. A total of 27 patients in the OPDIVO with chemotherapy arm, 31 patients in the OPDIVO with Ipilimumab arm, and 24 patients in the chemotherapy arm had PD-L1 CPS<1.
OS results for each comparison by PD-L1 CPS status were:
· OPDIVO with Chemotherapy vs. Chemotherapy: unstratified OS HR was 0.69 (95% CI: 0.56, 0.84) for PD-L1 CPS≥1 subgroup and 0.98 (95% CI: 0.50, 1.95) for PD-L1 CPS<1 subgroup.
· OPDIVO with Ipilimumab vs. Chemotherapy: unstratified OS HR was 0.76 (95% CI: 0.62, 0.93) for PD-L1 CPS≥1 subgroup and 1.0 (95% CI: 0.52, 1.94) for PD-L1 CPS<1 subgroup.
Previously Treated Unresectable Advanced, Recurrent or Metastatic Esophageal Squamous Cell Carcinoma (ESCC)
ATTRACTION-3 was a multicenter, randomized (1:1), active-controlled, open‑label trial in patients with unresectable advanced, recurrent, or metastatic ESCC, who were refractory or intolerant to at least one fluoropyrimidine- and platinum‑based regimen. The trial enrolled patients regardless of PD-L1 status, but tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory. The trial excluded patients who were refractory or intolerant to taxane therapy, had brain metastases that were symptomatic or required treatment, had autoimmune disease, used systemic corticosteroids or immunosuppressants, or had apparent tumor invasion of organs adjacent to the esophageal tumor or had stents in the esophagus or respiratory tract. Patients were randomized to receive OPDIVO 240 mg by intravenous infusion over 30 minutes every 2 weeks or investigator’s choice of taxane chemotherapy consisting of docetaxel (75 mg/m2 intravenously every 3 weeks) or paclitaxel (100 mg/m2 intravenously once a week for 6 weeks followed by 1 week off).
Randomization was stratified by region (Japan vs. Rest of World), number of organs with metastases (≤1 vs. ≥2), and PD-L1 status (≥1% vs. <1% or indeterminate). Patients were treated until disease progression, assessed by the investigator per RECIST v1.1, or unacceptable toxicity. The tumor assessments were conducted every 6 weeks for 1 year, and every 12 weeks thereafter. The major efficacy outcome measure was OS. Additional efficacy outcome measures were ORR and PFS as assessed by the investigator using RECIST v1.1 and DOR.
A total of 419 patients were randomized; 210 to the OPDIVO arm and 209 to the investigator’s choice arm (docetaxel: 31%, paclitaxel: 69%). The trial population characteristics were: median age 65 years (range: 33 to 87), 53% were ³65 years of age, 87% were male, 96% were Asian and 4% were White. Sixty-seven percent of patients had received one prior systemic therapy regimen and 26% had received two prior systemic therapy regimens prior to enrolling in ATTRACTION‑3. Baseline ECOG performance status was 0 (50%) or 1 (50%).
ATTRACTION-3 demonstrated a statistically significant improvement in OS for patients randomized to OPDIVO as compared with investigator’s choice of taxane chemotherapy. OS benefit was observed regardless of PD-L1 expression level. The minimum follow-up was 17.6 months. Efficacy results are shown in Table 66 and Figure 25.
Table 66: Efficacy Results - ATTRACTION-3
| OPDIVO | Docetaxel or Paclitaxel |
Overall Survivala |
|
|
Deaths (%) | 160 (76%) | 173 (83%) |
Median (months) | 10.9 (9.2, 13.3) | 8.4 (7.2, 9.9) |
Hazard ratio (95% CI)b | 0.77 (0.62, 0.96) | |
p-valuec | 0.0189 | |
Overall Response Rated | 33 (19.3) | 34 (21.5) |
(95% CI) | (13.7, 26.0) | (15.4, 28.8) |
Complete response (%) | 1 (0.6) | 2 (1.3) |
Partial response (%) | 32 (18.7) | 32 (20.3) |
Median duration of response (months) (95% CI) | 6.9 (5.4, 11.1) | 3.9 (2.8, 4.2) |
p-valuee | 0.6323 | |
Progression-free Survivala,f |
|
|
Disease progression or death (%) | 187 (89) | 176 (84) |
Median (months) (95% CI) | 1.7 (1.5, 2.7) | 3.4 (3.0, 4.2) |
Hazard ratio (95% CI)b | 1.1 (0.9, 1.3) | |
a Based on ITT analysis.
b Based on a stratified proportional hazards model.
c Based on a stratified log-rank test.
d Based on Response Evaluable Set (RES) analysis, n=171 in OPDIVO group and n=158 in investigator’s choice group.
e Based on stratified Cochran-Mantel-Haenszel test; p-value not significant.
f PFS not tested due to pre-specified hierarchical testing strategy.
Figure 25: Overall Survival - ATTRACTION-3
Of the 419 patients, 48% had PD-L1 positive ESCC, defined as ≥1% of tumor cells expressing PD-L1. The remaining 52% had PD-L1 negative ESCC defined as <1% of tumor cells expressing PD-L1.
In a pre-specified exploratory analysis by PD-L1 status, the hazard ratio (HR) for OS was 0.69 (95% CI: 0.51, 0.94) with median survivals of 10.9 and 8.1 months for the OPDIVO and investigator’s choice arms, respectively, in the PD-L1 positive subgroup. In the PD-L1 negative subgroup, the HR for OS was 0.84 (95% CI: 0.62, 1.14) with median survivals of 10.9 and 9.3 months for the OPDIVO and investigator’s choice arms, respectively.
Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma
CHECKMATE-649 was a randomized, multicenter, open-label trial in patients (n=1581) with previously untreated advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. The trial enrolled patients regardless of PD-L1 status, and tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory. The trial excluded patients who were known human epidermal growth factor receptor 2 (HER2) positive or had untreated CNS metastases. Patients were randomized to receive OPDIVO in combination with chemotherapy (n=789) or chemotherapy (n=792). Patients received one of the following treatments:
- OPDIVO 240 mg in combination with mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) every 2 weeks or mFOLFOX6 every 2 weeks.
- OPDIVO 360 mg in combination with CapeOX (capecitabine and oxaliplatin) every 3 weeks or CapeOX every 3 weeks.
Patients were treated until disease progression, unacceptable toxicity, or up to 2 years. In patients who received OPDIVO in combination with chemotherapy and in whom chemotherapy was discontinued, OPDIVO monotherapy was allowed to be given at 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks up to 2 years after treatment initiation.
Randomization was stratified by tumor cell PD-L1 status (≥1% vs. <1% or indeterminate), region (Asia vs. US vs. Rest of World), ECOG performance status (0 vs. 1), and chemotherapy regimen (mFOLFOX6 vs. CapeOX). The major efficacy outcome measures, assessed in patients with PD-L1 CPS ≥5, were PFS assessed by BICR and OS. Additional efficacy outcome measures included OS and PFS in patients with PD-L1 CPS ≥1 and in all randomized patients, and ORR and DOR as assessed by BICR in patients with PD-L1 CPS ≥1 and ≥5, and in all randomized patients. Tumor assessments were conducted per RECIST v1.1 every 6 weeks up to and including week 48, then every 12 weeks thereafter.
The trial population characteristics were: median age 61 years (range: 18 to 90), 39% were ³65 years of age, 70% were male, 24% were Asian, and 69% were White, and 1% were Black. Baseline ECOG performance status was 0 (42%) or 1 (58%). Seventy percent of patients had adenocarcinoma tumors in the stomach, 16% in the gastroesophageal junction, and 13% in the esophagus.
CHECKMATE-649 demonstrated a statistically significant improvement in OS and PFS for patients with PD-L1 CPS ≥5. Statistically significant improvement in OS was also demonstrated for all randomized patients. The minimum follow-up was 12.1 months. Efficacy results are shown in Table 67 and Figures 26, 27, and 28.
Table 67: Efficacy Results - CHECKMATE-649
| OPDIVO and mFOLFOX6 | mFOLFOX6 | OPDIVO and mFOLFOX6 | mFOLFOX6 | OPDIVO and mFOLFOX6 | mFOLFOX6 |
| All Patients | PD-L1 CPS ≥1 | PD-L1 CPS ≥5 | |||
Overall Survival | ||||||
Deaths (%) | 544 (69) | 591 (75) | 434 (68) | 492 (75) | 309 (65) | 362 (75) |
Median (months) (95% CI) | 13.8 (12.6, 14.6) | 11.6 (10.9, 12.5) | 14.0 (12.6, 15.0) | 11.3 (10.6, 12.3) | 14.4 (13.1, 16.2) | 11.1 (10.0, 12.1) |
Hazard ratio (95% CI)a | 0.80 (0.71, 0.90) | 0.77 (0.68, 0.88) | 0.71 (0.61, 0.83) | |||
p-valueb | 0.0002 | <0.0001 | <0.0001 | |||
Progression-free Survivalc | ||||||
Disease progression or death (%) | 559 (70.8) | 557 (70.3) | 454 (70.8) | 472 (72.1) | 328 (69.3) | 350 (72.6) |
Median (months) (95% CI) | 7.7 (7.1, 8.5) | 6.9 (6.6, 7.1) | 7.5 (7.0, 8.4) | 6.9 (6.1, 7.0) | 7.7 (7.0, 9.2) | 6.0 (5.6, 6.9) |
Hazard ratio (95% CI)a | 0.77 (0.68, 0.87) | 0.74 (0.65, 0.85) | 0.68 (0.58, 0.79) | |||
p-valueb | -e | -e | <0.0001 | |||
Overall Response Rate, n (%)c,d | 370 (47) | 293 (37) | 314 (49) | 249 (38) | 237 (50) | 184 (38) |
(95% CI) | (43, 50) | (34, 40) | (45, 53) | (34, 42) | (46, 55) | (34, 43) |
Complete response (%) | 78 (10) | 52 (7) | 65 (10) | 42 (6) | 55 (12) | 34 (7) |
Partial response (%) | 292 (37) | 241 (30) | 249 (39) | 207 (32) | 182 (38) | 150 (31) |
Duration of Response (months)c,d | ||||||
Median (95% CI) Range | 8.5 (7.2, 9.9) 1.0+, 29.6+ | 6.9 (5.8, 7.2) 1.2+, 30.8+ | 8.5 (7.7, 10.3) 1.1+, 29.6+ | 6.9 (5.8, 7.6) 1.2+, 30.8+ | 9.5 (8.1, 11.9) 1.1+, 29.6+ | 6.9 (5.6, 7.9) 1.2+, 30.8+ |
a Based on stratified Cox proportional hazard model.
b Based on stratified log-rank test.
c Assessed by BICR.
d Based on confirmed response.
e Not evaluated for statistical significance.
In an exploratory analysis in patients with PD-L1 CPS<1 (n=265), the median OS was 13.1 months (95% CI: 9.8, 16.7) for the OPDIVO and chemotherapy arm and 12.5 months (95% CI: 10.1, 13.8) for the chemotherapy arm, with a stratified HR of 0.85 (95% CI: 0.63, 1.15).
In an exploratory analysis in patients with PD-L1 CPS<5 (n=606), the median OS was 12.4 months (95% CI: 10.6, 14.3) for the OPDIVO and chemotherapy arm and 12.3 months (95% CI: 11.0, 13.2) for the chemotherapy arm, with a stratified HR of 0.94 (95% CI: 0.78, 1.14).
Figure 26: Overall Survival (All Patients) - CHECKMATE-649
Figure 27: Overall Survival (PD-L1 CPS ≥1) - CHECKMATE-649
Figure 28: Overall Survival (PD-L1 CPS ≥5) - CHECKMATE-649
5.2 Pharmacokinetic properties
Nivolumab pharmacokinetics (PK) was assessed using a population PK approach for both single-agent OPDIVO and OPDIVO with ipilimumab. The PK of nivolumab was studied in patients over a dose range of 0.1 mg/kg to 20 mg/kg administered as a single dose or as multiple doses of OPDIVO as a 60-minute intravenous infusion every 2 or 3 weeks. The exposure to nivolumab increases dose proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 weeks. The predicted exposure of nivolumab after a 30-minute infusion is comparable to that observed with a 60-minute infusion. Steady-state concentrations of nivolumab were reached by 12 weeks when administered at 3 mg/kg every 2 weeks, and systemic accumulation was 3.7-fold.
Distribution
The geometric mean volume of distribution at steady state (Vss) and coefficient of variation (CV%) is 6.8 L (27.3%).
Elimination
Nivolumab clearance (CL) decreases over time, with a mean maximal reduction from baseline values (CV%) of 24.5% (47.6%) resulting in a geometric mean steady-state clearance (CLss) (CV%) of 8.2 mL/h (53.9%) in patients with metastatic tumors; the decrease in CLss is not considered clinically relevant. Nivolumab clearance does not decrease over time in patients with completely resected melanoma, as the geometric mean population clearance is 24% lower in this patient population compared with patients with metastatic melanoma at steady state.
The geometric mean elimination half-life (t1/2) is 25 days (77.5%).
Specific Populations
The following factors had no clinically important effect on the clearance of nivolumab: age (29 to 87 years), weight (35 to 160 kg), sex, race, baseline LDH, PD-L1 expression, solid tumor type, tumor size, renal impairment (eGFR ≥ 15 mL/min/1.73 m2), and mild (total bilirubin [TB] less than or equal to the ULN and AST greater than ULN or TB greater than 1 to 1.5 times ULN and any AST) or moderate hepatic impairment (TB greater than 1.5 to 3 times ULN and any AST). Nivolumab has not been studied in patients with severe hepatic impairment (TB greater than 3 times ULN and any AST).
Pediatric Patients
The exposures of nivolumab in pediatric patients 12 years of age or older are comparable to those in adults at the recommended dosage [See Posology and Method of Administration (4.2).]
5.3 Preclinical safety data
Carcinogenesis, Mutagenesis
No studies have been performed to assess the potential of nivolumab for carcinogenicity or genotoxicity.
Impairment of Fertility
Fertility studies have not been performed with nivolumab. In 1-month and 3-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs; however, most animals in these studies were not sexually mature.
Animal Toxicology and/or Pharmacology
In animal models, inhibition of PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. M. tuberculosis–infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-1 knockout mice have also shown decreased survival following infection with lymphocytic choriomeningitis virus.
· Mannitol
· Pentetic acid
· Polysorbate 80
· Sodium chloride
· Sodium citrate dihydrate
· Water for Injection, USP
· May contain hydrochloric acid and/or sodium hydroxide to adjust pH to 6.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. OPDIVO should not be infused concomitantly in the same intravenous line with other medicinal products.
Store OPDIVO under refrigeration at 2°C to 8°C. Protect OPDIVO from light by storing in the original package until time of use. Do not freeze or shake.
OPDIVO is available as follows:
Carton Contents:
- One 40 mg/4 mL (10 mg/mL) single-dose vial
- One 100 mg/10 mL (10 mg/mL) single-dose vial
Visually inspect for particulate matter and discoloration. OPDIVO is a clear to opalescent, colorless to pale-yellow solution. Discard if cloudy, discolored, or contains extraneous particulate matter other than a few translucent-to-white, proteinaceous particles. Do not shake.
Preparation
· Withdraw the required volume of OPDIVO and transfer into an intravenous container.
· Dilute OPDIVO with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare an infusion with a final concentration ranging from 1 mg/mL to 10 mg/mL. The total volume of infusion must not exceed 160 mL.
· For adult and pediatric patients with body weight 40 kg or greater, do not exceed a total volume of infusion of 160 mL.
· For adult and pediatric patients with body weight less than 40 kg, do not exceed a total volume of infusion of 4 mL/kg of body weight.
· Mix diluted solution by gentle inversion. Do not shake.
· Discard partially used vials or empty vials of OPDIVO.
· The product does not contain a preservative.
Storage of Infusion
· After preparation, store the diluted solution either:
· at room temperature and room light for no more than 8 hours from the time of preparation to end of the infusion. Discard diluted solution if not used within 8 hours from the time of preparation; or
· under refrigeration at 2°C to 8°C and protected from light for no more than 7 days from the time of preparation to end of infusion. Discard diluted solution if not used within 7 days from the time of preparation.
· Do not freeze.
PATIENT COUNSELING INFORMATION
Advise the patient to read the patient information leaflet.
Immune-Mediated Adverse Reactions
Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and withholding or discontinuation of OPDIVO, including:
· Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath [see Special warnings and precautions for use (4.4)].
· Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Special warnings and precautions for use (4.4)].
· Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding [see Special warnings and precautions for use (4.4)].
· Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism, and diabetes mellitus [see Special warnings and precautions for use (4.4)].
· Nephritis and Renal Dysfunction: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis including decreased urine output, blood in urine, swelling in ankles, loss of appetite, and any other symptoms of renal dysfunction [see Special warnings and precautions for use (4.4)].
· Skin Adverse Reactions: Advise patients to contact their healthcare provider immediately for rash [see Special warnings and precautions for use (4.4)].
· Encephalitis: Advise patients to contact their healthcare provider immediately for neurological signs or symptoms of encephalitis [see Special warnings and precautions for use (4.4)].
Infusion-Related Reactions
· Advise patients of the potential risk of infusion-related reactions [see Special warnings and precautions for use (4.4)].
Complications of Allogeneic HSCT
· Advise patients of potential risk of post-transplant complications [see Special warnings and precautions for use (4.4)].
Females of Reproductive Potential
· Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Special warnings and precautions for use (4.4)] and Fertility, pregnancy and lactation (4.6)].
· Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months following the last dose of OPDIVO [see Fertility, pregnancy and lactation (4.6)].
Lactation
· Advise women not to breastfeed during treatment with OPDIVO and for 5 months after the last dose [see Fertility, pregnancy and lactation (4.6)].